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Can we say that the source of the most circulatory regulation in the human is the nervous system?

Can we say that the source of the most circulatory regulation in the human is the nervous system?


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local regulation of blood flow and Baroreceptors, both stimulate the neurons and send messages to the brain. so can we say that the source of the most circulatory regulation in the human is the nervous system?


Homeostasis and Regulation in the Human Body

The human body is made up of trillions of cells that all work together for the maintenance of the entire organism. While cells, tissues, and organs may perform very different functions, all the cells in the body are similar in their metabolic needs. Maintaining a constant internal environment by providing the cells with what they need to survive (oxygen, nutrients, and removal of waste) is necessary for the well-being of individual cells and of the entire body. The many processes by which the body controls its internal environment are collectively called homeostasis. The complementary activity of major body systems maintains homeostasis.

Homeostasis

Homeostasis refers to stability, balance, or equilibrium within a cell or the body. It is an organism’s ability to keep a constant internal environment. Homeostasis is an important characteristic of living things. Keeping a stable internal environment requires constant adjustments as conditions change inside and outside the cell. The adjusting of systems within a cell is called homeostatic regulation. Because the internal and external environments of a cell are constantly changing, adjustments must be made continuously to stay at or near the set point (the normal level or range). Homeostasis can be thought of as a dynamic equilibrium rather than a constant, unchanging state.

Feedback Regulation Loops

The endocrine system plays an important role in homeostasis because hormones regulate the activity of body cells. The release of hormones into the blood is controlled by a stimulus. For example, the stimulus either causes an increase or a decrease in the amount of hormone secreted. Then, the response to a stimulus changes the internal conditions and may itself become a new stimulus. This self-adjusting mechanism is called feedback regulation.

Feedback regulation occurs when the response to a stimulus has an effect of some kind on the original stimulus. The type of response determines what the feedback is called. Negative feedback occurs when the response to a stimulus reduces the original stimulus. Positive feedback occurs when the response to a stimulus increases the original stimulus.

Thermoregulation: A Negative Feedback Loop

Negative feedback is the most common feedback loop in biological systems. The system acts to reverse the direction of change. Since this tends to keep things constant, it allows the maintenance of homeostatic balance. For instance, when the concentration of carbon dioxide in the human body increases, the lungs are signaled to increase their activity and exhale more carbon dioxide, (your breathing rate increases). Thermoregulation is another example of negative feedback. When body temperature rises, receptors in the skin and the hypothalamus sense the temperature change. The temperature change (stimulus) triggers a command from the brain. This command, causes a response (the skin makes sweat and blood vessels near the skin surface dilate), which helps decrease body temperature. Figure 1 shows how the response to a stimulus reduces the original stimulus in another of the body’s negative feedback mechanisms.

Figure 1: Control of blood glucose level is an example of negative feedback. Blood glucose concentration rises after a meal (the stimulus). The hormone insulin is released by the pancreas, and it speeds up the transport of glucose from the blood and into selected tissues (the response). Blood glucose concentrations then decrease, which then decreases the original stimulus. The secretion of insulin into the blood is then decreased.

Positive feedback is less common in biological systems. Positive feedback acts to speed up the direction of change. An example of positive feedback is lactation (milk production). As the baby suckles, nerve messages from the mammary glands cause the hormone prolactin, to be secreted by the pituitary gland. The more the baby suckles, the more prolactin is released, which stimulates further milk production.

Not many feedback mechanisms in the body are based on positive feedback. Positive feedback speeds up the direction of change, which leads to increasing hormone concentration, a state that moves further away from homeostasis.

System Interactions

Each body system contributes to the homeostasis of other systems and of the entire organism. No system of the body works in isolation and the well-being of the person depends upon the well-being of all the interacting body systems. A disruption within one system generally has consequences for several additional body systems. Most of these organ systems are controlled by hormones secreted from the pituitary gland, a part of the endocrine system. Table 1 summarizes how various body systems work together to maintain homeostasis.

Main examples of homeostasis in mammals are as follows:

• The regulation of the amounts of water and minerals in the body. This is known as osmoregulation. This happens primarily in the kidneys.
• The removal of metabolic waste. This is known as excretion. This is done by the excretory organs such as the kidneys and lungs.
• The regulation of body temperature. This is mainly done by the skin.
• The regulation of blood glucose level. This is mainly done by the liver and the insulin and glucagon secreted by the pancreas in the body.

Table 1: Types of Homeostatic Regulation in the Body

Endocrine System

The endocrine system, shown in Figure 2, includes glands which secrete hormones into the bloodstream. Hormones are chemical messenger molecules that are made by cells in one part of the body and cause changes in cells in another part of the body. The endocrine system regulates the metabolism and development of most body cells and body systems through feedback mechanisms. For example, Thyrotropin-Releasing Hormone (TRH) and Thyroid Stimulating Hormone (TSH) are controlled by a number of negative feedback mechanisms. The endocrine glands also release hormones that affect skin and hair color, appetite, and secondary sex characteristics of males and females.

Figure 2: The endocrine system controls almost every other body system through feedback mechanisms. Most of the mechanisms of the endocrine system are negative feedback.

The endocrine system has a regulatory effect on other organ systems in the human body. In the muscular system, hormones adjust muscle metabolism, energy production, and growth. In the nervous system, hormones affect neural metabolism, regulate fluid and ion concentration and help with reproductive hormones that influence brain development.

Urinary System

Toxic wastes build up in the blood as proteins and nucleic acids are broken down and used by the body. The urinary system rids the body of these wastes. The urinary system is also directly involved in maintaining proper blood volume. The kidneys also play an important role in maintaining the correct salt and water content of the body. External changes, such as a warm weather, that lead to excess fluid loss trigger feedback mechanisms that act to maintain the body’s fluid content by inhibiting fluid loss. The kidneys also produce a hormone called erythropoietin, also known as EPO, which stimulates red blood cell production.

Reproductive System

The reproductive system does little for the homeostasis of the organism. The reproductive system relates instead to the maintenance of the species. However, sex hormones do have an effect on other body systems, and an imbalance in sex hormones can lead to various disorders. For example, a woman whose ovaries are removed early in life is at higher risk of developing osteoporosis, a disorder in which bones are thin and break easily. The hormone estrogen, produced by the ovaries, is important for bone growth. Therefore, a woman who does not produce estrogen will have impaired bone development.

Disruption of Homeostasis

Many homeostatic mechanisms keep the internal environment within certain limits (or set points). When the cells in your body do not work correctly, homeostatic balance is disrupted. Homeostatic imbalance may lead to a state of disease. Disease and cellular malfunction can be caused in two basic ways: by deficiency (cells not getting all they need) or toxicity (cells being poisoned by things they do not need). When homeostasis is interrupted, your body can correct or worsen the problem, based on certain influences. In addition to inherited (genetic) influences, there are external influences that are based on lifestyle choices and environmental exposure. These factors together influence the body’s ability to maintain homeostatic balance. The endocrine system of a person with diabetes has difficulty maintaining the correct blood glucose level. A diabetic needs to check their blood glucose levels many times during the day, as shown in Figure 3, and monitor daily sugar intake.

Figure 3: A person with diabetes has to monitor their blood glucose carefully. This glucose meter analyses only a small drop of blood.

Internal Influences: Heredity

Genetics: Genes are sometimes turned off or on due to external factors which we have some control over. Other times, little can be done to prevent the development of certain genetic diseases and disorders. In such cases, medicines can help a person’s body regain homeostasis. An example is the metabolic disorder Type 1 diabetes, which is a disorder where the pancreas is no longer producing adequate amounts of insulin to respond to changes in a person’s blood glucose level. Insulin replacement therapy, in conjunction with carbohydrate counting and careful monitoring of blood glucose concentration, is a way to bring the body’s handling of glucose back into balance. Cancer can be genetically inherited or be due to a mutation caused by exposure to toxin such as radiation or harmful drugs. A person may also inherit a predisposition to develop a disease such as heart disease. Such diseases can be delayed or prevented if the person eats nutritious food, has regular physical activity, and does not smoke.

External Influences: Lifestyle

Nutrition: If your diet lacks certain vitamins or minerals your cells will function poorly, and you may be at risk to develop a disease. For example, a menstruating woman with inadequate dietary intake of iron will become anemic. Hemoglobin, the molecule that enables red blood cells to transport oxygen, requires iron. Therefore, the blood of an anemic woman will have reduced oxygen-carrying capacity. In mild cases symptoms may be vague (e.g. fatigue), but if the anemia is severe the body will try to compensate by increasing cardiac output, leading to weakness, irregular heartbeats and in serious cases, heart failure.

Physical Activity: Physical activity is essential for proper functioning of our cells and bodies. Adequate rest and regular physical activity are examples of activities that influence homeostasis. Lack of sleep is related to a number of health problems such as irregular heartbeat, fatigue, anxiety, and headaches. Being overweight and obesity, two conditions that are related to poor nutrition and lack of physical activity greatly affect many organ systems and their homeostatic mechanisms. Being overweight or obese increases a person’s risk of developing heart disease, Type 2 diabetes, and certain forms of cancer. Staying fit by regularly taking part in aerobic activities such as walking, shown in Figure 4, has been shown to help prevent many of these diseases.

Figure 4: Adding physical activity to your routine can be as simple as walking for a total of 60 minutes a day, five times a week.

Mental Health: Your physical health and mental health are inseparable. Our emotions cause chemical changes in our bodies that have various effects on our thoughts and feelings. Negative stress (also called distress) can negatively affect mental health. Regular physical activity has been shown to improve mental and physical well-being, and helps people to cope with distress. Among other things, regular physical activity increases the ability of the cardiovascular system to deliver oxygen to body cells, including the brain cells. Medications that may help balance the amount of certain mood-altering chemicals within the brain are often prescribed to people who have mental and mood disorders. This is an example of medical help in stabilizing a disruption in homeostasis.

Environmental Exposure

Any substance that interferes with cellular function and causes cellular malfunction is a cellular toxin. There are many different sources of toxins, for example, natural or synthetic drugs, plants, and animal bites. Air pollution, another form of environmental exposure to toxins is shown in Figure 5. A commonly seen example of an exposure to cellular toxins is by a drug overdose. When a person takes too much of a drug that affects the central nervous system, basic life functions such as breathing and heartbeat are disrupted. Such disruptions can results in coma, brain damage, and even death.

Figure 5: Air pollution can cause environmental exposure to cellular toxins such as mercury.

The six factors described above have their effects at the cellular level. A deficiency or lack of beneficial pathways, whether caused by an internal or external influence, will almost always result in a harmful change in homeostasis. Too much toxicity also causes homeostatic imbalance, resulting in cellular malfunction. By removing negative health influences and providing adequate positive health influences, your body is better able to self-regulate and self-repair, which maintains homeostasis.


The Endocannabinoid System, Our Universal Regulator

The endocannabinoid system (ECS) plays a very important role in the human body for our survival. This is due to its ability to play a critical role in maintaining the homeostasis of the human body, which encompasses the brain, endocrine, and immune system, to name a few. ECS is a unique system in multiple dimensions. To begin with, it is a retrograde system functioning post- to pre-synapse, allowing it to be a “master regulator” in the body. Secondly, it has a very wide scope of influence due to an abundance of cannabinoid receptors located anywhere from immune cells to neurons. Finally, cannabinoids are rapidly synthesized and degraded, so they do not stay in the body for very long in high amounts, possibly enabling cannabinoid therapy to be a safer alternative to opioids or benzodiazepines. This paper will discuss how ECS functions through the regulation of neurotransmitter function, apoptosis, mitochondrial function, and ion-gated channels. The practical applications of the ECS, as well as the avenues for diseases such as epilepsy, cancer, amyotrophic lateral sclerosis (ALS), and autism, which have no known cure as of now, will be explored.

Despite various medical advances, there are still many more functions of the human body to uncover. Some of the less effective treatments lie within the field of mental health, due to the lack of accuracy and availability of tests for neurotransmitter function as well as apoptotic activity. The existing neurotransmitter tests utilize metabolites in urine (Hinz, Stein, Trachte, & Ucini 2010) however, their applicability is currently very limited. We have not been able to show that the neurotransmitter levels measured in urine are as accurate as the actual levels in the central nervous system (CNS) or peripheral nervous system (PNS).

Apoptotic diseases such as cancer, acquired immune deficiency syndrome (AIDS), ALS, and autism, are all without an effective cure at the moment, and they seem to have similar pathology which involves neurotransmitter, mitochondrial, and apoptotic dysfunction (Favaloro, Allocati, Graziano, Di Lio, & De Laurenzi 2012).

The ECS, unlike the CNS, PNS, and circulatory system, is one of the most understudied systems in the human body. It has been documented that ECS is directly involved with various roles in apoptosis, neurotransmitter levels, and homeostasis (Basavarajappa, Nixon, & Arancio, 2009). ECS seems to carry a stigma because of the word “cannabis.” In this paper, functions and possible benefits of ECS will be discussed.

The Endocannbinoid System Structure and Function

With all the complex cell signals, genetic mutations, and outside influences, how do we manage to stay at homeostasis? The answer is the endocannabinoid system. It is present nearly everywhere in the human body and functions by maintaining the homeostasis of the human body (Alger, 2013). This is achieved through a negative feedback loop which works by the activation of a postsynaptic neuron synthesizing and releasing the endocannabinoids as they target various cannabinoid (CB) receptors.

These CB receptors are G-protein-coupled receptors (Gambi et al., 2005), which allow them to directly influence the incoming signals. This functions as an “override” signal, which differs from most other cells. As other cells have signal modifiers that can do anything from amplifying to diverging signals, the neuron is “over-riding” those cells. For example, a fracture in the toe would result in cell death. The resulting lymphatic response would increase blood flow and the migration of white blood cells to the surrounding areas. The ECS would then recognize the excess lymphatic signals, and after deciding that there is no longer a need for the increase of inflammation, the CB receptors in the surrounding immune cells and tissues will begin to bind with cannabinoids and start to slowly reduce these inflammatory responses.

A similar process occurs with pain signals in the brain. The binding and stimulation of CB1 receptors will upregulate the gamma-aminobutyric acid (GABA) neurotransmitters, thereby reducing pain signals throughout the brain. There are two main receptors in the ECS: the CB1 and CB2 receptors. CB1 receptors are located primarily within brain cells (including but not limited to the hippocampus, amygdala, and hypothalamus), and are not as densely expressed in the CNS, PNS, and the immune system. On the other hand, the CB2 receptors are located primarily in the CNS, PNS, immune system, and within white blood cells. Additionally, the existence of CB3 receptors is also hypothesized (Iqbal, 2007). These receptors will most likely be vast, with each one having a unique specialization despite being found in multiple locations throughout the body (Mazarnes, & Carracosa 2006).

The Endocannibinoids

There are multiple known endocannabinoids that play a role in the ECS. All of them seem to play a role in anti-proliferative, anti-inflammatory, and anti-metastatic effects (Madia & Daeninck, 2016). Additionally, it appears that they have a role in neurotransmitter, immune system, and mitochondrial function. There are two main endocannabinoids: anandamide and 2-archidonyl glycerol (2-AG).

Anandamide is an endocannabinoid in the human body. With the chemical formula C22H37NO2, it is referred to as the “bliss molecule.” It can be released when one eats chocolate after a craving (Mackie, 2008). Anandamide may be a very important cannabinoid to manipulate for controlling pain stimuli. This is due to an interesting quality of anandamide in which the concentration of anandamide dictates the type and number of receptors activated. Anandamide also has the ability to make or break short-term connections between nerve cells that directly affect memory. There is speculation whether anandamide dulls and removes not only physical pain but psychological discomfort as well. If so, this could be utilized to help individuals with posttraumatic stress disorder (PTSD). This argument has particular merit as repression is a well-known coping mechanism (De Petrocellis et al., 1998). Furthermore, anandamide has been shown to have anti-proliferative effects in breast cancer. It has also been shown to bind with a strong affinity to the CB1 receptors, which may play a greater role in the analgesic effects of the endocannabinoids.

2-Arachidonyl glycerol is the most prevalent endocannabinoid in the human body. Its chemical structure is quite similar to anandamide, having the same carbon backbone but a different R-group, C23H38O4 (Gonsiorek, 2000). It is considered a full agonist of both the CB1 and CB2 receptors, playing a major role in ECS. Due to its high expression in peripheral immune cells, it seems to play a large role in anti-inflammation through immune suppression. Nonetheless, it also functions as a psychoactive endocannabinoid when it binds to CB1 receptors within brain cells.

Gertsch, Pertwee, and DiMarzo (2010) show that cannabis contains two very prevalent phyto-cannabinoids that target each CB receptor: tetrahydrocannabinol (THC) which is the active phyto-cannabinoid in cannabis primarily targeting the CB1 receptor, and β-caryophyllene (a terpene), which selectively targets the CB2 receptor (Prakash, Pandey, Amcaoglu, Venkatesh, & Nagarkatti, 2009). These phyto-cannabinoids can mimic the action of endocannabinoids. However, it is hard to measure exactly how many of each of the CB receptors are being stimulated, and how much of each phyto-cannabinoid is entering the blood stream. However, since the cannabis plant can essentially function as a mass stimulation to the ECS, the body recognizes these phyto-cannabinoids as endocannabinoids.

Lipid Metabolism

The ECS runs through adipose tissue, demonstrating its role in adipogenesis, lipogenesis, and glucose uptake, all of which are stimulated by the CB1 receptor. Cannabinoids are unique in that they are rapidly synthesized as well as broken down soon after being used, which creates fewer long-term side effects. The two main enzymes that break down these endocannabinoids are fatty amide acid hydrolase (FAAH) and monoacylglycerol lipase (MAGL) (Petrosino & Dimarzo, 2010). The endogenous cannabinoid system is extremely ubiquitous due to the fact that cannabinoids are both rapidly synthesized and degraded, which creates less long-term side effects.

Due to the previously stated ubiquitous nature, the effect of having the cannabinoid levels constantly altered for an extended period of time is not well known (Long et al., 2009). What is known is that FAAH is the preferred enzyme for the degradation of anandamide, whereas MAGL is the preferred enzyme for the degradation of 2-AG. Inhibitors of these enzymes have demonstrated success in stimulating the ECS. It is possible that by inhibiting one or both of these enzymes, the levels of various neurotransmitter could be adjusted and kept at a steady state for an extended period of time. This can be accomplished by preventing the hydrolysis of certain endo/phyto-cannabinoids that stimulate the release of various neurotransmitters.

Apoptotic Pathway

Apoptosis, which is the programmed death of cells, is an essential component of the cell cycle. This has multiple implications for the human body, such as maintaining the homeostasis or eradicating potentially dangerous cancer cells. While many of the proteins involved are known, the exact mechanisms of apoptosis are yet to be elucidated. Apoptosis is not the only manner in which cell death occurs the other large contributor to cell death is necrosis (Elmore, 2007). However, unlike apoptosis, necrosis is highly toxic to cells and results in inflammation due to cellular lysis, which proceeds with cell death.

Apoptosis is generally caused by the activation of various caspases, a family of enzymes that play an essential role in apoptosis. Caspase-2, 8, 9, and 10 are considered initiators, whereas caspase-3, 6, and 7 are executioners. The three main pathways in which apoptosis can occur are extrinsic, intrinsic, and the perforin/granzyme pathway.

In the extrinsic pathway, there is a clustering of receptors as well as the binding with their homologous ligand. For example, Fas ligand to receptor binding results in the adapter Fas-associated via death domain (FAA) and the binding of tumor necrosis factor (TNF) to its corresponding receptor. This then binds TNF receptor-associated death domain (TRADD adapter protein) which associates with procaspase-8 through dimerization of the death effector domain. This results in death-inducing signaling complex (DISC) which catalyzes the caspase-8. Caspase-8 acts as an initiator which then triggers the execution phase.

On the other hand, the intrinsic pathway does not require external stimuli. Instead, it relies on intracellular stimuli producing negative or positive signals. The signals can vary from loss of apoptotic suppression to loss of growth factors and toxins, among others. These stimuli cause changes in the mitochondria, resulting in mitochondrial permeability transition (MPT), loss of transmembrane potential, and the release of two main groups of apoptotic proteins, which then activate various caspases such as caspase-3 and 9.

The granzyme pathway is unique due to granzyme B’s ability to cleave proteins at aspartate residues, resulting in direct activation of caspase-3, an executioner, thereby skipping the initiation phase of apoptosis. Additionally, this pathway plays a large role in T-cell- activated apoptosis. In a study conducted by Amcaoglu, Ashok, Ugra, Mitzi, and Prakash (2010), THC has been shown to cause cells to undergo enhanced and spontaneous apoptosis both in vitro and in vivo. Interestingly, mice treated with only THC had a higher rate of apoptosis than mice treated with both THC and mitogen (a substance that influences mitosis or cell division). Additionally, it was noted that active lymphocytes downregulated expression of CB2 receptors. However, CB1 agonists failed to have a significant impact in reducing THC-activated apoptosis, whereas CB2 agonists blocked the THC-induced apoptosis. This demonstrates the role of ECS in controlling various disease states and inflammation.

Mitochondrial Function

The mitochondria are responsible for converting carbohydrates and fatty acids into adenosine triphosphate (ATP) and providing energy for cells (Cooper, 2000). Uniquely, the mitochondria contain their own DNA. Similar to nuclear genomes, mutations can occur in mitochondrial genomes and cause disorders.

One of the main functions of ECS is modulating mitochondrial function. This can be accomplished through a variety of shared pathways. For example, a calcium-based pathway demonstrates how anandamide and 2-AG can modulate intracellular free calcium (Nunn, Guy, & Bell, 2012). At low doses, anandamide produces expected result displaying anxiolytic (anti-anxiety) effects. However, at high doses, anandamide may activate transient receptor potential cation channel subfamily V member 1 (TRPV1), which would produce the opposite effect by upregulating mitochondrial function, thereby increasing anxiety. Anandamide has the ability to induce such effects due to its ability to bind with CB1 receptors at postsynaptic junctions, monitoring the opening of voltage-gated Ca2+ channels. This demonstrates that the modulation of calcium is more complicated than originally thought.

The ECS may also modulate mitochondria through redox reactions. Once again, this is another example of how ECS uses CB1 and CB2 receptors as a system of checks and balances within itself. This is evident due to the ability of CB1 receptors to increase reactive oxygen species (ROS), which results in an inflammatory cascade and mitochondrial stress. However, CB2 decreases ROS, resulting in the opposite effect. For example, an individual with a diagnosis of cancer may require an increase of mitochondrial stress to stimulate appetite, and modulation of both receptors through various agonists/antagonists might help control the activity of the mitochondria. There are many other pathways, including the ceramide link and mechanistic target of rapamycin (mTOR) pathways that play a role in mitochondrial function which will be discussed later on in the paper.

An interesting fact regarding the mitochondria and their structure is the location of FAAH on the mitochondria, which is the primary fatty acid that degrades anandamide. This appears to be a strategic placement since anandamide plays a role in suppressing mitochondrial function. This placement allows the mitochondria to always be able to degrade anandamide if there was an excess of anandamide in the mitochondria. It would not be surprising to find that FAAH and MAGL (fatty acids) are located on various parts of the cellular infrastructure in which the ECS plays an important role in regulating. It cannot be emphasized enough how important the concentration is, as it pertains to their effect on mitochondrial function. Low concentrations of cannabinoids seem to benefit mitochondrial lifespan, function, ROS, and permeability, while it can cause serious damage to the mitochondria at higher concentrations.

Metabolic function and appetite have a direct association with mitochondrial function (Lipina, Irving, & Hundal, 2014). Selectively blocking the CB1 receptor was shown to have a profound effect on appetite and metabolic function, which may be of help to obese individuals. However, it also causes incredible mood changes including anxiety and depression. This illustrates one of the most important points of ECS, which is its interconnectivity. ECS plays a role in the modulation of so many functions that in an attempt to change one, we may end up altering so many other functions that we cause more harm than good. It is not medically sound to block an entire cannabinoid receptor type perhaps the focus should be on the individual pathways that are modulated by cannabinoid-receptor binding. For example, increasing FAAH located around the mitochondria could result in the degradation of anandamide, which has a negative impact on the mitochondria, while the remainder of anandamide can function separately and carry on its duties throughout the body.

ECS and Mental Illness

ECS is intriguing and relatively unexplored in terms of the role it plays in mental health. Manipulation of ECS might be beneficial in the treatment of schizophrenic patients. For example, in a clinical trial conducted with schizophrenic patients, anandamide levels were significantly higher in the blood of patients with acute schizophrenia when compared to healthy volunteers (7.79 ± 0.50 vs. 2.58 ± 0.28pmol/ml, De Marchi et al., 2003)

Anandamide is the second most common endocannabinoid and is extremely vital in the human body. The level of anandamide is an indicator of the acuity of the dysfunction of ECS as it relates to mental illness. Schizophrenia, as summarized by the National Institute for Mental Health (National Institute of Mental Health [NIMH], 2016b), is “a chronic and severe mental disorder that affects how a person thinks, feels, and behaves.” People with schizophrenia may seem like they have lost touch with reality. Although schizophrenia is not as common as other mental disorders, the symptoms can be very disabling.

One can conclude that the more severe the mental illness, the greater the dysfunction in the ECS. If we view mental illness on a continuum instead of separate entities, it would lend a more accurate view of mental illness. Some of the more common mental illnesses such as depression, anxiety, and schizophrenia, share similarities and generally contain overlapping symptoms when diagnosed. Sadness, suicidal thoughts, body dysmorphia, and panic attacks are the general symptoms of these conditions. The biggest difference is not the way someone feels, but the intensity of their feelings.

Based on this information, it would be logical to assume mental illnesses can be connected through a series of similar neurochemical imbalances and the resulting symptoms. It is important to note that some symptoms may intensify due to the positive or negative feedback loops as a result of the imbalances in various neurotransmitters, which give the appearance of a “new disease.” For example, schizophrenic patients may appear to be solely depressed or anxious due to the mass dysfunction of neurotransmitters. These can then be amplified and may produce new symptoms such as hallucinations or extreme mania. However, that does not mean the chemical imbalances that cause depression or anxiety are gone they are simply amplified, or in some instances, reduced. It appears that the different mental health illnesses may be interconnected in a web or network, which is maintained through neurotransmitter function. By testing and observing neurotransmitter function, one could obtain coordinates to see where in the web or network the issues with neurotransmitter are occurring. Errors in the ECS, which influence mood and perception, would help to explain these errors and malfunctions. Therefore, mental illness may be influenced by errors in the ECS as a result of miscommunication of the neurotransmitters. Since the ECS functions as a retrograde system, it can have a direct influence on the associated neurotransmitters. Therefore, targeting ECS might be a more effective treatment method than only addressing the neurotransmitters themselves. The current approach to addressing mental illness focuses on manipulating neurotransmitter release however, this seems more like a band-aid treatment than an actual cure. Treating the underlying homeostatic issues through the ECS, thereby restoring neurotransmitter function, appears to be a more permanent solution.

Current Treatments

For the treatment of depression, the most common anti-depressants are selective serotonin reuptake inhibitors (SSRI) and other reuptake inhibitors (NIMH, 2016a). Various reuptake inhibitors function by preventing the reuptake of their specific neurotransmitters in the brain, allowing them to stay longer in the synapses and increase their concentrations. However, this is only a temporary fix that does not address the underlying cause of multiple neurotransmitter imbalances. Additionally, SSRIs only targets serotonin, yet most cases of depression are due to multiple neurotransmitter imbalances. Focusing solely on one neurotransmitter is not likely to result in improvement and could easily exacerbate the disease. The fact that SSRIs may increase depression and suicidal thoughts for some patients suggests that it may not be the best treatment option.

For anxiety, SSRIs are a common treatment however, benzodiazepines are becoming the most prevalent form of treatment. The primary action of benzodiazepines is to bind to a pocket formed by GABA’s alpha and gamma subunits (Griffin III, Kaye, Bueno, & Kaye, 2013). This results in the conformational change in the GABA-A receptor, which induces the inhibitory effect of GABA. GABA is highly concentrated in the limbic system, which is the system most closely associated with addiction. This is one of the most prevalent issues with benzodiazepines, as focusing solely on GABA increases the chance for addiction. Benzodiazepine’s short half-life contributes to the extremely addictive nature of the drug. Benzodiazepines are listed as a schedule IV drug (United States Drug Enforcement Administration, n.d.), which implies that along with its ability to treat disease, it has a relatively low potential for abuse. However, this is not the case. According to the National Institute on Drug Abuse (2017), there were approximately 8,700 overdose-related deaths in 2015, which was a 4.3-fold increase from 2002.

New Directions

As stated above, there are clear concerns about the way mental illnesses are being treated. One of the largest concerns is related to a lack of neurotransmitter testing to determine the contributions of various neurotransmitters to mental illness. From there, future treatments should address the underlying causes without the utilization of addictive substances.

GABA has a unique relationship with the ECS (Sigel et al., 2011). When 2-AG is activated, it enhances the effects of GABA by causing an increase of the GABA neurotransmitters in the human body (Manzanares & Carracosa, 2006). However, when the CB1 receptor is activated by endocannabinoids or phyto-cannabinoids, it inhibits GABA. This is not surprising as the ECS is responsible for a majority of the body’s homeostatic functions. If one were to activate the body’s ECS by introducing an influx of endocannabinoids or phyto-cannabinoids, and predetermine which receptors were activated, it could give us bi-directional control over GABA that current drugs fail to offer.

For example, to increase an individual’s GABA levels, one could take a CB1 inhibitor such as rimonabant, which prevents CB1 activation. This would result in 2-AG becoming the primary endocannabinoid synthesized due to 2-AG’s affinity to the CB2 receptor, subsequently increasing GABA concentration. To decrease GABA, one could utilize an agonist of MAGL to increase degradation of 2-AG. This would result in having a stable level of anandamide concentration with a much lower 2-AG concentration.

Treatments that would directly affect the ECS might be more beneficial than medication currently used to treat mental illnesses. This is due to the ability of cannabinoids to correct the neurochemical imbalances by attacking the source of the issue, rather than just attempting to alleviate the symptoms.

Apoptotic Functions and Potential Cures for HIV, Cancer, Autism, ALS, and Epilepsy

HIV is generally caused by increased apoptosis of primarily CD4+ and CD8+ T-cells. Initially, HIV stimulates various cellular cascades that eventually leads to permanent conformational changes (Simon, Ho, & Karim, 2006). Not only is apoptosis increased in HIV glycoproteins, but cellular activation is increased as well, resulting in an increase in turnover of T-cells. This seems to indicate an increase of T-cell destruction rather than a lack of T-cell production.

T-cells are very important for the immune response against pathogens, extracellular parasites, and other possible viral or bacterial organisms (Zhu & William, 2008). Unlike cancer, apoptosis is not suppressed, but rather excited in the presence of HIV. However, one of the incredible mechanisms regarding ECS is that even though it is considered a “negative feedback loop” as a result of varying receptors and cannabinoids, it appears that it is possible to both decrease and increase apoptosis. Hypothetically, if one were able to reduce T-cell apoptosis which occurs in the early stage of HIV, one might be able to reverse the process completely and eradicate the virus.

Cancer is a result of multiple genetic mutations that allow cells to multiply uncontrollably, evade apoptosis, become immortal, and undergo metastasis. Some of the genes are proto-oncogenes, such as Ras (Lodish, Berk, & Zipursky, 2000), while others are tumor suppressor genes (TSG) (Zhu, et al, 2015), such as BRCA1 and BRCA2 (Lowe & Lin, 2000). p53 is another TSG, which also plays an extremely important role as a cell-cycle checkpoint protein involving cycle arrest.

Common forms of cancer treatment include radiotherapy, which blasts cancer cells with radiation in hopes of eradicating all of the cancer cells, is not a sustainable treatment. There are other pharmacological interventions. For example, Gleevec (imatinib mesylate) has been shown to be especially effective (RX list, 2017) as an anti-cancer treatment. Gleevec functions as a small molecule kinase inhibitor. As the action of Gleevec is targeted, it is a much safer approach. However, this renders its use very selective, such that it has a high success rate only if the Philadelphia chromosomal abnormality is present (Pray, 2008). An additional problem with drugs such as Gleevec is their effect on the p-glycoprotein (Schinkel, 1999), which functions as a “selective pump” in the blood-brain barrier and other various sanctuaries in the body. However, this function backfires with various anti-cancer drugs, as it tends to pump them out in an attempt to detoxify the body.

The ECS should be evaluated as a possible alternative to treat cancer. One of the keys to eradicating cancer is the selective induction of apoptosis. THC has been shown to trigger apoptosis, as mentioned earlier. If we could determine the appropriate cannabinoids (THC, THCA, CBD, 2-AG, etc.) associated with cancer, we could take a step-wise approach to neutralize specific cancers. This would be accomplished by injecting the specific cannabinoids into the cancerous tumor via a virus or vector. Since CB2 has the largest effect on apoptosis, we could enhance CB2 binding by utilizing an antagonist of MAGL. This would prevent the cannabinoids that generally bind to the CB2 receptor from being degraded, resulting in an increased and prolonged concentration of cannabinoids within the blood stream.

The specific fatty acids to be blocked or enhanced may vary from cancer to cancer, as would the cannabinoids used in treatment. This may be an effective way to induce apoptosis inside the cell, which would eradicate cancer while minimizing adverse reactions commonly associated with conventional chemotherapy. This could prove to be very successful due to the fact that once certain mutations in the cell have resulted in cancer, the ability to process a normal signal from p53 and other TSG/oncogenes is lost. Through utilizing the ECS to override these cancerous cells, these cells may be induced to attend to the new apoptotic signals.

Autism, or autism spectrum disorder (ASD), is a disease which involves both physical and behavioral changes. The cells in the CNS which are most affected are the GABAergic Purkinje neurons (Goodenowe & Pastural, 2011). These neurons are the only output of the cerebellar cortex and play a vital role in the function and design of the cerebellum circuits. The loss of these specific GABAergic neurons is one of the primary causes of autism. While apoptosis gone awry could be the source of the disappearance of these Purkinje neurons, this is typically not the case. The most common catalysts which are responsible for their destruction are alcohol and other toxins (Sudarov, 2013). However, since the neurons are GABAergic, the ECS would not be able to replicate these particular neurons, but manipulation of the system could allow us to modulate the GABA signals that should occur within the deceased Purkinje neurons.

Another indicator of autism is mass mitochondrial dysfunction, which can be detected in numerous ways, including but not limited to: plasma lactate levels, carnitine levels, and glutathione levels (Goodenowe & Pastural, 2011). Interestingly, the Purkinje neuron has been associated with certain mitochondrial disorders that signal autism. Excessive amounts of glutamate formed by microglia can form around Purkinje neurons. This can be caused by presynaptic depolarization of climbing fiber neurons, which play a role in massive action potential spikes (Ohtsuki, Piochon, & Hansel, 2009) and synaptic spillover, which can result in glutamate toxicity.

Additionally, there is an interesting gender bias in autism, with prevalence nearly four times as much in prepubescent males than in prepubescent females. This is due to a four-fold increase of estrogen in females, which seems to function as a protective mechanism for mitochondria, especially B-estradiol. It is therefore not surprising that the mitochondrial malfunctions that are protected best by B-estradiol are related to glutamate toxicity.

In addition to their role with the GABA/glutamate neurotransmitters, the ECS has also been shown to play a direct role in controlling mitochondrial malfunction. As previously mentioned, the ECS is known to modulate many pathways, including Ca2+ channels, Kir, MAPK, e/iNOS, mTor, and ceramide production. This demonstrates that the ECS has a firm “hold” over mitochondrial production (Nunn, Guy, & Bell, 2012). Through these different pathways, various endocannabinoids are expressed, exhibiting a system of diverse responses within these pathways. These range from increasing/decreasing apoptosis, increasing nNOD in neurons, and decreasing iNOS in astrocytes.

There is also a plethora of other controls within these pathways which are just as important with regards to mitochondrial production. However, one of the most important pathways is mTOR, which controls mitochondrial function and lifespan. Although the ECS is generally considered anti-proliferative, throughout the mTOR pathway (specifically CB2 activation), it has been demonstrated that the ECS can become proliferative, solely through low-level activation. This activation might provide treatment for mitochondrial dysfunction in autism as a result of the ECS’s mass control over the mitochondrial pathways.

A key to altering mitochondrial function in patients with autism could be FAAH, which is the primary enzyme responsible for degrading anandamide and THC (National Institute of Neurological Disorders and Stroke, 2013). FAAH inhibitors have been known to show analgesic, anti-inflammatory, and anti-depressant properties in mice. This makes sense since with FAAH lowered or removed, the endogenous cannabinoid anandamide would be more prevalent in the bloodstream, and it has been known to produce the aforementioned effects through interactions with various parts of the brain and immune cells. This could be a possible course of treatment in individuals with autism, since their mitochondria may be downregulated. Inhibiting FAAH would allow for prolonged interaction with anandamide, which at the right concentration, will upregulate mitochondrial function.

Amyotrophic Lateral Sclerosis (ALS)

ALS is a neurodegenerative disease that can affect nerve cells in the brain and spinal cord (specifically motor neurons), resulting in their death. Consequently, the brain loses the ability to control muscles, including those of lung and heart (Ahn, Johnson, & Benjamin, 2009). ALS is only understood up to a point, with multiple theories in agreement that cell death contributes to this process. One of the more salient theories is that apoptosis plays a large role in ALS, and is responsible for the death of motor neurons (Sathasivam, Ince, & Shaw, 2001). It has been reported that in ALS, there are changes in p53 proteins and the Bcl-2 family.

Cancer is another disease that exhibits mutations similar to these proteins however, opposite effects take place. In cancer, there is uncontrolled cell growth, which contrasts with the uncontrolled cell death found in ALS. However, the cell death in ALS specifically targets the motor neurons. In a study conducted by Ranganathan and Bowser (2010), p53 levels were found elevated significantly in the spinal cord, but not so in the motor neurons. This finding might partially explain the death of motor neurons in ALS, and suggests that ALS may be a two-tiered disease.

Another presenting issue in most ALS patients is their glutamate levels (Foran & Trotti, 2009). Glutamate excitotoxicity is very common in neurodegenerative diseases such as ALS. Various glutamate transporters known as the excitatory amino acid transporter (EAAT) family have a large role in glutamate regulation, although structural differences exist. EEAT-2 appears to be important in glutamate transport due to its abundance in the brain and within the CNS. In postmortem studies of ALS patients, there is a clear downregulation of EEAT-2 present within the ventral horn of the spinal cord, demonstrating the presence of glutamate excitotoxicity.

Excitotoxicity is modulated primarily through the Ca2+ pathways, which was discussed in the section on autism, and is influenced by the ECS. So, it is not a surprise that glutamate is one of the neurotransmitters that the ECS influences. ALS appears to be the result of apoptosis and abnormalities with glutamate transport. It seems that one may act as a catalyst for the other. It is possible that the increase of apoptotic activity in caspases-8 (initiator) and 3 (executioner) can lead to the increased apoptosis of motor neurons. This phenomenon then results in a dysregulation of glutamate transport, subsequently causing excitotoxicity which can be the primary factor in morphing ALS into a deadly disease.

Our hypothesis is that untreated ALS has an exponential growth curve, despite not being apparent in the review conducted. Once a certain percentage of motor neurons have died, there is an increase in dysregulation of proteins (such as EEAT-2), which result in the inevitable death of the ALS patients. We believe that downregulation of apoptosis through the ECS will at some point lead to an eventual cure. Another hypothesis is that some other potential pathways may reduce the emission of glutamate, even after the downregulation of various proteins.

Epilepsy is a complex disease in which there are multiple theorized causes, such as epigenetics, neurotransmitter imbalance, ion-gated channel dysfunction, etc. However, we will be focusing on the previously mentioned variables and their effect on epilepsy.

Epileptic seizures are not all the same (Bromfield, Cavazos, & Sirven, 2006) there are partial seizures and generalized seizures. The main cause of epilepsy is the failure of the membrane to reach its equilibrium post-action potential (Bromfield et al., 2006). Action potentials are formed due to depolarization of the neuronal membrane, which prompts the release of neurotransmitters at the axon terminal. These are brought about by net positive changes in various ion fluxes such as the ligand or voltage-gated channels, or changes in intracellular ion compartmentalization. There are eight types of neurotransmitters in the brain however, we will be focusing primarily on the major excitatory and inhibitory neurotransmitters, glutamate and GABA, respectively.

Neuronal excitability has many variables that can determine how large the excitatory and inhibitory effect can be, including the modulation of gene expression, type or number of gated channels, and changes in extracellular ion concentrations. However, we notice that a lot of these are modulated by the homeostatic functions of the ECS (Rosenberg, Tsien, Whalley, & Devinsky, 2015). There is a clear link between cannabis and its anticonvulsant properties, but it is important to note the difference between the exogenous cannabinoids in cannabis and the endogenous cannabinoids that the body produces (Alger, 2014). For example, it makes sense that the exogenous/phyto-cannabinoids have a much broader effect on our body. This effect can be referred as the “generalized cannabinoid arc.” When smoking marijuana, regardless of the strain, there are a series of effects that generally occur. This could be due to the fact that, although they mimic the endogenous cannabinoids in our body, they were not designed to modulate our various systems.

Since the cannabinoids are endogenous in nature, we would argue that every endocannabinoid and CB receptor play a specific role in the homeostatic function of the muscle, organelle, or cascade that it controls. So, despite the success thus far that has been achieved by treating epilepsy with cannabis, perhaps a more optimal treatment route would be to utilize the ECS directly. Despite the challenges, we believe that it would provide a more effective treatment for epilepsy. This raises the question of how we use the intricate pathways of ECS to manipulate the neurotransmitters and action potentials. Interestingly, the most efficient way to stimulate short-term endothelial CB (eCB) mobilization would be utilizing depolarizations of postsynaptic membranes that last from 1s to 10s. Action potentials are also depolarizations, specifically involving the neuronal membrane. If artificial stimulation of eCB is a similar process to these action potentials, it would make sense that the body’s natural response to these action potentials is to control them with ECS due to the homeostatic function of the systems.

One could hypothesize that an error within ECS could result in epilepsy. The most promising treatment for epilepsy may be utilizing the CB1 receptors located throughout the brain, specifically, for their response to action potentials and their ability to manipulate GABA in epilepsy. Regardless of whether the miscommunication in the ECS is the cause or simply a side effect of epilepsy, a possible path to curing it is through manipulating the ECS with a prolonged cannabinoid therapy. To achieve this, we must direct research into the specificity of each endocannabinoid and their respective receptors. Once we fully decode the ECS and its role with respect to epilepsy, we would be able to not only stop seizures, but also, through extended therapy, correct the errors causing the prolonged firing of action potentials which induce the occurrence of seizures.

The ECS is one of the, if not the most, important systems in our body. Its role in the homeostatic function of our body is undeniable, and its sphere of influence is incredible. Additionally, it also plays a major role in apoptotic diseases, mitochondrial function, and brain function.

Its contribution is more than maintaining homeostasis it also has a profound ability in regulation. Working in a retrograde fashion and with a generally inhibitory nature, ECS can act as a “kill switch.” However, it has been shown to play an inhibitory or stimulatory role based on the size of the influx of cannabinoids, resulting in a bimodal regulation. Furthermore, due to the nature of the rate of degradation of cannabinoids, it does not have as many long-term side effects as most of the current drugs on the market.

The ECS may not only provide answers for diseases with no known cures, but it could change the way we approach medicine. This system would allow us to change our focus from invasive pharmacological interventions (i.e. SSRIs for depression, benzodiazepines for anxiety, chemotherapies for cancer) to uncovering the mystery of why the body is failing to maintain homeostasis. Understanding the roles of ECS in these diseases confers a new direction for medicine which may eradicate the use of some of the less tolerable therapeutics.

Ahn, K., Johnson, D., & Cravatt, B. (2009). Fatty acid amide hydrolase as a potential therapeutic target for the treatment of pain and CNS disorders. Expert Opinions on Drug Discovery, 4(7), 763-764. doi:10.1517%2F17460440903018857

Alger, B. (2013). Getting High on the endocannabinoid system. Cerebrum: The Dana Forum on Brain Science, 14.

Alger, B. E. (2014). Seizing an Opportunity for the Endocannabinoid System. Epilepsy Currents, 14(5), 272-276. doi:10.5698/1535-7597-14.5.272

Amcaoglu, R., Ashok, C., Ugra, S., Mitzi, N., & Prakash, N. (2010). Cannabinoid-induced apoptosis in immune cells as a pathway to immunosuppression. Immunobiology, 215(8), 598-605. doi:10.1016/j.imbio.2009.04.001

Basavarajappa, B., Nixon, R., & Arancio, O. (2009). Endocannabinoid System: Emerging Role from Neurodevelopment to Neurodegeneration. Mini-Reviews in Medicinal Chemistry. 9(4). doi:10.2174/138955709787847921

Bromfield, E. B., Cavazos, J. E., & Sirven, J. I. (2006). Basic Mechanisms Underlying Seizures and Epilepsy. An Introduction to Epilepsy. West Hartford (CT): American Epilepsy Society.

Bromfield, E. B., Cavazos, J. E., & Sirven, J. I. (2006). Clinical Epilepsy. An Introduction to Epilepsy. West Hartford (CT): American Epilepsy Society.

Cooper, G. M. (2000). The Cell: A molecular Approach. Sunderland (Mass), Sinauer Associates.

De Marchi, N., De Petrocellis, L., Pierangelo, O., Fabiana, D., Filomena, F., & Di Marzo, V. (2003). Endocannabinoid signaling in the blood of patients with schizophrenia. Lipids in Health and Disease, 2(5). doi:10.1186/1476-511X-2-5

De Petrocellis, L., Palmisano, A., Melck, D., Bissogno, T., Laezza, C., Bifuclo, M., & Di Marzo, V. (1998). The endogenous cannabinoid anadamide inhibits human breast cancer cell proliferation. Proceedings National Academy of Science USA, 95(14), 8375-8380

Elmore, S. (2007). Apoptosis: A review of Programmed cell death. Toxicology Pathology, 35(4), 495-516. doi:10.1080/01926230701320337

Favaloro, B., Allocati, N., Graziano V., Di lio, C., & De Laurenzi. (2012). Role of Apoptosis in disease. Aging, 4(5), 330–349. doi:10.18632/aging.100459

Foran, E., & Trotti, D. (2009). Glutamate transporters and the excitotoxic path to motor neuron degeneration in amyotrophic lateral sclerosis. Antioxidants and Redox signaling, 11(7), 1587-1602. doi:10.1089/ars.2009.2444

Gambi, F., De Beradis, D., Sepede, G., Quartesan, R., Calcagni, E., Salerno, R. M., . Ferro, F. M. (2005). Cannabinoid receptors and their relationships with neuropsychiatric disorders. International Journal Immunopathology Pharmacology, 18(1), 15-9. doi:10.1177/039463200501800103

Gertsch, J., Pertwee, R., & DiMarzo, V. (2010). Phyto-cannabinoids beyond the Cannabis plant-do they exist? British Journal of Pharmacology, 160(3), 523-529. doi:10.1111/j.1476-5381.2010.00745.x

Gonsiorek, W., Lunn, C., Fan, X., Narula, S., Lundell, D., & Hipkin, R. W. (2000). Endocannabinoid 2-arachidonyl glycerol is a full agonist through human type 2 cannabinoid receptor: antagonism by anandamide. Molecular pharmacology, 57(5), 1045-50.

Goodenowe, D., & Pastural, E. (2011). The Biochemical Basis of Autistic Behavior and Pathology. Autism - A Neurodevelopmental Journey from Genes to Behaviour. Rijeka: Intech. doi:10.5772/18571

Griffin III, C., Kaye, A., Bueno, F., & Kaye, A. (2013). Benzodiazeprine Pharmacology and Central Nervous system-mediated effects. Ochsner Journal, 13(2), 214-223.

Hinz, M., Stein, A., Trachte G., & Uncini, T. (2010). Neurotransmitter testing of the urine: a comprehensive analysis. Dove Press, 2010(2), 177-183. doi:10.2147/RRU.S13370

Lipina, C., Irving, A., & Hundal, H. (2014). Mitochondria: a possible nexus for the regulation of energy homeostasis by the endocannabinoid system? American Journal of Physiology-Endocrinology and Metabolism, 307(1), 1-13. doi:10.1152/ajpendo.00100.2014

Lodish, H., Berk, A., & Zipursky, S. L. (2000). Proto-onco genes and tumor-supressor genes. Molecular Cell biology. New York: W.H. Freeman.

Long, J., Normura, D., Vann, R., Walentiny, M., Booker, L., Jin X., … Cravatt, B. (2009). Dual blockade of FAAh and MAGL identifies behavioral processes regulated by endocannabinoid crosstalk in vivo. Proceedings of the National Academy of Sciences of the United States of America, 106(48). doi:10.1073/pnas.0909411106

Lowe, S., & Lin, A. (2000). Apoptosis in Cancer. Carcinogenesis. Oxford Academic Journal, 21(3), 485-495.

Mackie, K. (2008). Cannabinoid receptors: where they are and what they do. Journal of Neuroendocrinology, 20, 10-14. doi:10.1111/j.1365-2826.2008.01671.x

Maida, V., & Daeninck, P. J. (2016). A user’s guide to cannabinoid therapies in oncology. Current Oncology. 23(6), 398–406. doi:10.3747/co.23.3487

Manzanares, J., & Carrascosa, A. (2006). Role of the cannabinoid system in pain control and therapeutic implications for the management of acute and chronic pain episodes. Current Neuropharmacology, 4(3), 239-257.

Manzanares, J., Julian, M., & Carracosa, A. (2006). Role of the Cannabinoid system in pain control and therapeutic implications for the management of acute and chronic pain episodes. Current neuropharmacology. 4(3), 239-257.

National Institute on Drug Abuse. (2017). Overdose Death Rates. Retrieved from https://www.drugabuse.gov/related-topics/trends-statistics/overdose-death-rates

National Institute of Mental Health. (2016a). Mental Health Medications. Retrieved from: https://www.nimh.nih.gov/health/topics/mental-health-medications/index.shtml

National Institute of Mental Health. (2016b). Schizophrenia. Retrieved from: https://www.nimh.nih.gov/health/topics/schizophrenia/index.shtml

National Institute of Neurological Disorders and Stroke. (2013). Amyotrophic Lateral Sclerosis (ALS) fact sheet. Retrieved from: https://www.ninds.nih.gov/-Disorders/Patient-Caregiver-Education/Fact-Sheets/Amyotrophic-Lateral-Sclerosis-ALS-Fact-Sheet

Nunn, A., Guy, G., & Bell, J. (2012). Endocannabinoids in neuroendopsychology: Multiphasic control of mitochondrial function. Philosophical Transactions B, 367(1607), 3342-3352. doi:10.1098/rstb.2011.0393

Ohtsuki, G., Piochon, C., & Hansel, C. (2009). Climbing Fiber Signaling and Cerebellar Gain Control. Frontiers in Cellular Neuroscience, 3, 4. doi:10.3389/neuro.03.004.2009

Omar, I. (2007). Endocannabinoid system pathophysiology of apidogenesis: current management of obesity. Personalized Medicine, 4(3), 307-319.

Petrosino, S., & Di Marzo, V. (2010). FAAH and MAGL inhibitors: therapeutic opportunities from regulating endocannabinoid levels. Current Opinion in Investigational Drugs, 11(1), 51-62.

Prakash, N., Pandey, R., Amcaoglu, R., Venkatesh, H., & Nagarkatti, M. (2009). Cannabinoids as novel anti-inflammatory drugs. Future Medicinal Chemistry, 1(7), 1333-1349. doi:10.4155/fmc.09.93

Pray, L. (2008). Gleevec: The Breakthrough in Cancer Treatment. Nature Education, 1(1), 37.

Ranganathan, S., & Bowser, R. (2010). p53 and Cell Cycle Protiens Participate in Spinal Motor Neuron Cell Death in ALS. The Open Pathology Journal, 4, 11-22. doi:10.2174/1874375701004010011

Rosenberg, E. C., Tsien, R. W., Whalley, B. J., & Devinsky, O. (2015). Cannabinoids and Epilepsy. Neurotheraputics, 12(4), 747-768. doi:10.1007/s13311-015-0375-5

RX List. (2017). Gleevec. Retrieved from: http://www.rxlist.com/gleevec-drug.htm

Sathasivam, S., Ince, P. G., & Shaw, P. J. (2001). Apoptosis in amyotrophic lateral sclerosis: a review of the evidence. Neuropathology and Applied Neurobiology, 27(4), 257-74.

Schinkel, A. H. (1999). P-Glycoprotien, a gatekeeper in the blood brain barrier. Advanced Drug Delivery Reviews, 36(2-3), 179-194.

Sigel, E., Baur, R., Racz, I., Smart, T. G., Zimmer, A., & Gertsch, J. (2011). The major central endocannabinoid directly acts at GABA(A) receptors. Proceedings of the National Academy of Science, 108(44), 18150-18155. doi:10.1073/pnas.1113444108

Simon, V., Ho, D., & Karim, Q. (2006). HIV/AIDS epidomology pathogensis, prevention, and treatment. Lancet, 368(9534), 489-504.

Sudarov, A. (2013). Defining the role of Cerebellar Purkinje cells in autism spectrum disorders. Cerebellum. 12(6), 950-95. doi:10.1007/s12311-013-0490-y

United States Drug Enforcement Administration. (n.d.). Drug Scheduling. Retrieved from https://www.dea.gov/druginfo/ds.shtml

Zhu, J., & William, P. (2008). CD4 T cells: fates, functions, and faults. Blood, 112(5), 1557-1569. doi:10.1182/blood-2008-05-078154

Zhu, K., Liu, Q., Zhou, Y., Tao, C., Zhongming, Z., Sun, J., & Xu, H. (2015). Oncogenes and tumor suppressor genes: comparative genomics and network perspectives. BMC Genomics, 6(7). doi:10.1186/1471-2164-16-S7-S8


What Is Hypothermia?

Another cold weather danger is hypothermia, which is when your body temperature drops dangerously low – below 95 degrees Fahrenheit. When this happens, your heart, nervous system, and other organs cannot work properly. If left untreated, hypothermia can lead to heart and respiratory system failure and death.

Symptoms of moderate to severe hypothermia include:

  • A lot of shivering or a halt in shivering
  • Lack of coordination
  • Slurred speech
  • Confusion
  • Weak pulse
  • Slow, shallow breathing
  • Drowsiness

Your body fights hypothermia by keeping your core as warm as possible. This causes a lack of circulation, especially to your body’s extremities like fingers and toes, which can result in frostbite.

Frostbite stages

There are three stages of frostbite – frostnip, superficial, and advanced.

  • Frostnip is the mildest form and earliest stage of frostbite. It may feel like pins and needles, throbbing, aching, or numbness.
  • The second stage of frostbite is superficial and can be identified by the skin turning white or very pale and hard. After rewarming treatment, the skin may appear blue or purple and fluid-filled blisters may appear.
  • Severe frostbite affects all layers of skin. You may lose sensation and ability to use joints or muscles. The affected skin may turn black and hard as the tissue dies, damaging tendons, muscles, nerves, and bone.

Frostnip can be treated at home by wrapping sterile dressings around the infected area. You should always seek medical attention if symptoms of superficial or severe frostbit occur. Other symptoms of frostbite include fever, dizziness, and generally feeling ill.

RELATED: Hypothermia Symptoms and First Aid Treatment

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Universal mechanism of regulation in plant cells discovered

All plant cells obtain their energy mainly from two organelles they contain -- chloroplasts (responsible for photosynthesis) and mitochondria (responsible for the biochemical cycle of respiration that converts sugars into energy). However, a large number of a plant cell's genes in its mitochondria and chloroplasts can develop defects, jeopardising their function. Nevertheless, plant cells evolved an amazing tool called the RNA editosome (a large protein complex) to repair these kinds of errors. It can modify defective messenger RNA that result from defective DNA by transforming (deamination) of certain mRNA nucleotides.

Automatic error correction in plant cells

Automatic error correction in plants was discovered about 30 years ago by a team headed by plant physiologist Axel Brennicke and two other groups simultaneously. This mechanism converts certain cytidine nucleotides in the messenger RNA into uridine in order to correct errors in the chloroplast DNA or mitochondrial DNA. RNA editing is therefore essential to processes such as photosynthesis and cellular respiration in plants. Years later, further studies showed that a group of proteins referred to as PPR proteins with DYW domains play a central role in plant RNA editing. These PPR proteins with DYW domains are transcribed in the cell nucleus and migrate through the cells to chloroplasts and mitochondria. However, they are inactive on their way to these organelles. Only once they are within the organelles do they become active and execute their function at a specific mRNA site. How this activation works, however, has been a mystery until now.

It doesn't work in a test tube

For many years, it was not possible to synthetically produce these DYW-type PPR proteins in the laboratory to study their function and structure more closely. Only now has a German-Japanese team headed by structural biologist and biochemist Dr. Gert Weber from the Joint Protein Crystallography Group at Helmholtz-Zentrum Berlin and Freie Universität Berlin succeeded in doing so.

Now: 3D structure of the key protein decoded

Prof. Mizuki Takenaka's group had previously been able to produce the DYW domain in bacteria. Takenaka has been conducting research at Kyoto University since 2018 and previously worked in Axel Brennicke's laboratory in Ulm, Germany. Tatiana Barthel (University of Greifswald and now at HZB) was then able to grow the first protein crystals of the DYW domain. A large number of these delicate crystals have now been analysed at the MX beamlines of BESSY II so that the three-dimensional architecture of the DYW domain could be decoded. "Thanks to the Joint Research Group co-located at HZB and FU Berlin, we have the capability of beam time for measurements very quickly when needed, which was crucial," says Dr. Manfred Weiss, who is responsible for the MX beamlines at BESSY II and co-author of the study.

Mechanism of activation discovered

This three-dimensional architecture has actually provided the crucial clue to the mechanism of DYW domain activation that applies to all plants. It is due to a zinc atom located in the centre of the DYW domain that can accelerate the deamination of cytidine to uridine like a catalyst. For this to happen, however, the zinc must be optimally positioned. The activation switch is provided by a very unusual gating domain in the immediate vicinity of the catalytic centre -- the structural analysis shows that this gating domain can assume two different positions, thereby switching the enzyme on or off. "The movement of the gating domain regulates the extent to which the zinc ion is available for the catalytic reaction," Weber explains.

A molecule like scissors

Now it has become clear why getting DYW-type PPR proteins to react with RNA in the test tube has been difficult until now: these PPR proteins are nominally inactive and require activation. In the plant cells, they are first produced in the cell nucleus and then very likely migrate in an inactivated state to the organelles, where they become activated. "This is ideal, because otherwise these molecules would be active along the way, altering various RNA molecules in an uncontrolled fashion harmful to the cell," says Weber.

Universal repair tool

This work is a breakthrough for plant molecular biology because it describes an additional level of sophisticated regulation in chloroplasts and mitochondria. The results are fundamental for plant science, but they could also play a role in our daily lives someday. The DYW domain might provide a useful tool for controllable and site-specific C-to-U and U-to-C RNA editing. This could open up new bioengineering and medical applications, such as reprogramming certain mitochondrial genes without changing a cell's nuclear DNA.


15.1 Divisions of the Autonomic Nervous System

The nervous system can be divided into two functional parts: the somatic nervous system and the autonomic nervous system. The major differences between the two systems are evident in the responses that each produces. The somatic nervous system causes contraction of skeletal muscles. The autonomic nervous system controls cardiac and smooth muscle, as well as glandular tissue. The somatic nervous system is associated with voluntary responses (though many can happen without conscious awareness, like breathing), and the autonomic nervous system is associated with involuntary responses, such as those related to homeostasis.

The autonomic nervous system regulates many of the internal organs through a balance of two aspects, or divisions. In addition to the endocrine system, the autonomic nervous system is instrumental in homeostatic mechanisms in the body. The two divisions of the autonomic nervous system are the sympathetic division and the parasympathetic division . The sympathetic system is associated with the fight-or-flight response , and parasympathetic activity is referred to by the epithet of rest and digest . Homeostasis is the balance between the two systems. At each target effector, dual innervation determines activity. For example, the heart receives connections from both the sympathetic and parasympathetic divisions. One causes heart rate to increase, whereas the other causes heart rate to decrease.

Interactive Link

Watch this video to learn more about adrenaline and the fight-or-flight response. When someone is said to have a rush of adrenaline, the image of bungee jumpers or skydivers usually comes to mind. But adrenaline, also known as epinephrine, is an important chemical in coordinating the body’s fight-or-flight response. In this video, you look inside the physiology of the fight-or-flight response, as envisioned for a firefighter. His body’s reaction is the result of the sympathetic division of the autonomic nervous system causing system-wide changes as it prepares for extreme responses. What two changes does adrenaline bring about to help the skeletal muscle response?

Sympathetic Division of the Autonomic Nervous System

To respond to a threat—to fight or to run away—the sympathetic system causes divergent effects as many different effector organs are activated together for a common purpose. More oxygen needs to be inhaled and delivered to skeletal muscle. The respiratory, cardiovascular, and musculoskeletal systems are all activated together. Additionally, sweating keeps the excess heat that comes from muscle contraction from causing the body to overheat. The digestive system shuts down so that blood is not absorbing nutrients when it should be delivering oxygen to skeletal muscles. To coordinate all these responses, the connections in the sympathetic system diverge from a limited region of the central nervous system (CNS) to a wide array of ganglia that project to the many effector organs simultaneously. The complex set of structures that compose the output of the sympathetic system make it possible for these disparate effectors to come together in a coordinated, systemic change.

The sympathetic division of the autonomic nervous system influences the various organ systems of the body through connections emerging from the thoracic and upper lumbar spinal cord. It is referred to as the thoracolumbar system to reflect this anatomical basis. A central neuron in the lateral horn of any of these spinal regions projects to ganglia adjacent to the vertebral column through the ventral spinal roots. The majority of ganglia of the sympathetic system belong to a network of sympathetic chain ganglia that runs alongside the vertebral column. The ganglia appear as a series of clusters of neurons linked by axonal bridges. There are typically 23 ganglia in the chain on either side of the spinal column. Three correspond to the cervical region, 12 are in the thoracic region, four are in the lumbar region, and four correspond to the sacral region. The cervical and sacral levels are not connected to the spinal cord directly through the spinal roots, but through ascending or descending connections through the bridges within the chain.

A diagram that shows the connections of the sympathetic system is somewhat like a circuit diagram that shows the electrical connections between different receptacles and devices. In Figure 15.2, the “circuits” of the sympathetic system are intentionally simplified.

To continue with the analogy of the circuit diagram, there are three different types of “junctions” that operate within the sympathetic system (Figure 15.3). The first type is most direct: the sympathetic nerve projects to the chain ganglion at the same level as the target effector (the organ, tissue, or gland to be innervated). An example of this type is spinal nerve T1 that synapses with the T1 chain ganglion to innervate the trachea. The fibers of this branch are called white rami communicantes (singular = ramus communicans) they are myelinated and therefore referred to as white (see Figure 15.3a). The axon from the central neuron (the preganglionic fiber shown as a solid line) synapses with the ganglionic neuron (with the postganglionic fiber shown as a dashed line). This neuron then projects to a target effector—in this case, the trachea—via gray rami communicantes , which are unmyelinated axons.

In some cases, the target effectors are located superior or inferior to the spinal segment at which the preganglionic fiber emerges. With respect to the “wiring” involved, the synapse with the ganglionic neuron occurs at chain ganglia superior or inferior to the location of the central neuron. An example of this is spinal nerve T1 that innervates the eye. The spinal nerve tracks up through the chain until it reaches the superior cervical ganglion , where it synapses with the postganglionic neuron (see Figure 15.3b). The cervical ganglia are referred to as paravertebral ganglia , given their location adjacent to prevertebral ganglia in the sympathetic chain.

Not all axons from the central neurons terminate in the chain ganglia. Additional branches from the ventral nerve root continue through the chain and on to one of the collateral ganglia as the greater splanchnic nerve or lesser splanchnic nerve . For example, the greater splanchnic nerve at the level of T5 synapses with a collateral ganglion outside the chain before making the connection to the postganglionic nerves that innervate the stomach (see Figure 15.3c).

Collateral ganglia , also called prevertebral ganglia , are situated anterior to the vertebral column and receive inputs from splanchnic nerves as well as central sympathetic neurons. They are associated with controlling organs in the abdominal cavity, and are also considered part of the enteric nervous system. The three collateral ganglia are the celiac ganglion , the superior mesenteric ganglion , and the inferior mesenteric ganglion (see Figure 15.2). The word celiac is derived from the Latin word “coelom,” which refers to a body cavity (in this case, the abdominal cavity), and the word mesenteric refers to the digestive system.

An axon from the central neuron that projects to a sympathetic ganglion is referred to as a preganglionic fiber or neuron, and represents the output from the CNS to the ganglion. Because the sympathetic ganglia are adjacent to the vertebral column, preganglionic sympathetic fibers are relatively short, and they are myelinated. A postganglionic fiber —the axon from a ganglionic neuron that projects to the target effector—represents the output of a ganglion that directly influences the organ. Compared with the preganglionic fibers, postganglionic sympathetic fibers are long because of the relatively greater distance from the ganglion to the target effector. These fibers are unmyelinated. (Note that the term “postganglionic neuron” may be used to describe the projection from a ganglion to the target. The problem with that usage is that the cell body is in the ganglion, and only the fiber is postganglionic. Typically, the term neuron applies to the entire cell.)

One type of preganglionic sympathetic fiber does not terminate in a ganglion. These are the axons from central sympathetic neurons that project to the adrenal medulla , the interior portion of the adrenal gland. These axons are still referred to as preganglionic fibers, but the target is not a ganglion. The adrenal medulla releases signaling molecules into the bloodstream, rather than using axons to communicate with target structures. The cells in the adrenal medulla that are contacted by the preganglionic fibers are called chromaffin cells . These cells are neurosecretory cells that develop from the neural crest along with the sympathetic ganglia, reinforcing the idea that the gland is, functionally, a sympathetic ganglion.

The projections of the sympathetic division of the autonomic nervous system diverge widely, resulting in a broad influence of the system throughout the body. As a response to a threat, the sympathetic system would increase heart rate and breathing rate and cause blood flow to the skeletal muscle to increase and blood flow to the digestive system to decrease. Sweat gland secretion should also increase as part of an integrated response. All of those physiological changes are going to be required to occur together to run away from the hunting lioness, or the modern equivalent. This divergence is seen in the branching patterns of preganglionic sympathetic neurons—a single preganglionic sympathetic neuron may have 10–20 targets. An axon that leaves a central neuron of the lateral horn in the thoracolumbar spinal cord will pass through the white ramus communicans and enter the sympathetic chain, where it will branch toward a variety of targets. At the level of the spinal cord at which the preganglionic sympathetic fiber exits the spinal cord, a branch will synapse on a neuron in the adjacent chain ganglion. Some branches will extend up or down to a different level of the chain ganglia. Other branches will pass through the chain ganglia and project through one of the splanchnic nerves to a collateral ganglion. Finally, some branches may project through the splanchnic nerves to the adrenal medulla. All of these branches mean that one preganglionic neuron can influence different regions of the sympathetic system very broadly, by acting on widely distributed organs.

Parasympathetic Division of the Autonomic Nervous System

The parasympathetic division of the autonomic nervous system is named because its central neurons are located on either side of the thoracolumbar region of the spinal cord (para- = “beside” or “near”). The parasympathetic system can also be referred to as the craniosacral system (or outflow) because the preganglionic neurons are located in nuclei of the brain stem and the lateral horn of the sacral spinal cord.

The connections, or “circuits,” of the parasympathetic division are similar to the general layout of the sympathetic division with a few specific differences (Figure 15.4). The preganglionic fibers from the cranial region travel in cranial nerves, whereas preganglionic fibers from the sacral region travel in spinal nerves. The targets of these fibers are terminal ganglia , which are located near—or even within—the target effector. These ganglia are often referred to as intramural ganglia when they are found within the walls of the target organ. The postganglionic fiber projects from the terminal ganglia a short distance to the target effector, or to the specific target tissue within the organ. Comparing the relative lengths of axons in the parasympathetic system, the preganglionic fibers are long and the postganglionic fibers are short because the ganglia are close to—and sometimes within—the target effectors.

The cranial component of the parasympathetic system is based in particular nuclei of the brain stem. In the midbrain, the Edinger–Westphal nucleus is part of the oculomotor complex, and axons from those neurons travel with the fibers in the oculomotor nerve (cranial nerve III) that innervate the extraocular muscles. The preganglionic parasympathetic fibers within cranial nerve III terminate in the ciliary ganglion , which is located in the posterior orbit. The postganglionic parasympathetic fibers then project to the smooth muscle of the iris to control pupillary size. In the upper medulla, the salivatory nuclei contain neurons with axons that project through the facial and glossopharyngeal nerves to ganglia that control salivary glands. Tear production is influenced by parasympathetic fibers in the facial nerve, which activate a ganglion, and ultimately the lacrimal (tear) gland. Neurons in the dorsal nucleus of the vagus nerve and the nucleus ambiguus project through the vagus nerve (cranial nerve X) to the terminal ganglia of the thoracic and abdominal cavities. Parasympathetic preganglionic fibers primarily influence the heart, bronchi, and esophagus in the thoracic cavity and the stomach, liver, pancreas, gall bladder, and small intestine of the abdominal cavity. The postganglionic fibers from the ganglia activated by the vagus nerve are often incorporated into the structure of the organ, such as the mesenteric plexus of the digestive tract organs and the intramural ganglia.

Chemical Signaling in the Autonomic Nervous System

Where an autonomic neuron connects with a target, there is a synapse. The electrical signal of the action potential causes the release of a signaling molecule, which will bind to receptor proteins on the target cell. Synapses of the autonomic system are classified as either cholinergic , meaning that acetylcholine (ACh) is released, or adrenergic , meaning that norepinephrine is released. The terms cholinergic and adrenergic refer not only to the signaling molecule that is released but also to the class of receptors that each binds.

The cholinergic system includes two classes of receptor: the nicotinic receptor and the muscarinic receptor . Both receptor types bind to ACh and cause changes in the target cell. The nicotinic receptor is a ligand-gated cation channel and the muscarinic receptor is a G protein–coupled receptor . The receptors are named for, and differentiated by, other molecules that bind to them. Whereas nicotine will bind to the nicotinic receptor, and muscarine will bind to the muscarinic receptor, there is no cross-reactivity between the receptors. The situation is similar to locks and keys. Imagine two locks—one for a classroom and the other for an office—that are opened by two separate keys. The classroom key will not open the office door and the office key will not open the classroom door. This is similar to the specificity of nicotine and muscarine for their receptors. However, a master key can open multiple locks, such as a master key for the Biology Department that opens both the classroom and the office doors. This is similar to ACh that binds to both types of receptors. The molecules that define these receptors are not crucial—they are simply tools for researchers to use in the laboratory. These molecules are exogenous , meaning that they are made outside of the human body, so a researcher can use them without any confounding endogenous results (results caused by the molecules produced in the body).

The adrenergic system also has two types of receptors, named the alpha (α)-adrenergic receptor and beta (β)-adrenergic receptor . Unlike cholinergic receptors, these receptor types are not classified by which drugs can bind to them. All of them are G protein–coupled receptors. There are two types of α-adrenergic receptors, termed α1, and α2, and there are three types of β-adrenergic receptors, termed β1, β2 and β3. An additional aspect of the adrenergic system is that there is a second signaling molecule called epinephrine . The chemical difference between norepinephrine and epinephrine is the addition of a methyl group (CH3) in epinephrine. The prefix “nor-” actually refers to this chemical difference, in which a methyl group is missing.

The term adrenergic should remind you of the word adrenaline, which is associated with the fight-or-flight response described at the beginning of the chapter. Adrenaline and epinephrine are two names for the same molecule. The adrenal gland (in Latin, ad- = “on top of” renal = “kidney”) secretes adrenaline. The ending “-ine” refers to the chemical being derived, or extracted, from the adrenal gland. A similar construction from Greek instead of Latin results in the word epinephrine (epi- = “above” nephr- = “kidney”). In scientific usage, epinephrine is preferred in the United States, whereas adrenaline is preferred in Great Britain, because “adrenalin” was once a registered, proprietary drug name in the United States. Though the drug is no longer sold, the convention of referring to this molecule by the two different names persists. Similarly, norepinephrine and noradrenaline are two names for the same molecule.

Having understood the cholinergic and adrenergic systems, their role in the autonomic system is relatively simple to understand. All preganglionic fibers, both sympathetic and parasympathetic, release ACh. All ganglionic neurons—the targets of these preganglionic fibers—have nicotinic receptors in their cell membranes. The nicotinic receptor is a ligand-gated cation channel that results in depolarization of the postsynaptic membrane. The postganglionic parasympathetic fibers also release ACh, but the receptors on their targets are muscarinic receptors, which are G protein–coupled receptors and do not exclusively cause depolarization of the postsynaptic membrane. Postganglionic sympathetic fibers release norepinephrine, except for fibers that project to sweat glands and to blood vessels associated with skeletal muscles, which release ACh (Table 15.1).

Sympathetic Parasympathetic
Preganglionic Acetylcholine → nicotinic receptor Acetylcholine → nicotinic receptor
Postganglionic Norepinephrine → α- or β-adrenergic receptors
Acetylcholine → muscarinic receptor (associated with sweat glands and the blood vessels associated with skeletal muscles only
Acetylcholine → muscarinic receptor

Signaling molecules can belong to two broad groups. Neurotransmitters are released at synapses, whereas hormones are released into the bloodstream. These are simplistic definitions, but they can help to clarify this point. Acetylcholine can be considered a neurotransmitter because it is released by axons at synapses. The adrenergic system, however, presents a challenge. Postganglionic sympathetic fibers release norepinephrine, which can be considered a neurotransmitter. But the adrenal medulla releases epinephrine and norepinephrine into circulation, so they should be considered hormones.

What are referred to here as synapses may not fit the strictest definition of synapse. Some sources will refer to the connection between a postganglionic fiber and a target effector as neuroeffector junctions neurotransmitters, as defined above, would be called neuromodulators. The structure of postganglionic connections are not the typical synaptic end bulb that is found at the neuromuscular junction, but rather are chains of swellings along the length of a postganglionic fiber called a varicosity (Figure 15.5).

Everyday Connection

Fight or Flight? What About Fright and Freeze?

The original usage of the epithet “fight or flight” comes from a scientist named Walter Cannon who worked at Harvard in 1915. The concept of homeostasis and the functioning of the sympathetic system had been introduced in France in the previous century. Cannon expanded the idea, and introduced the idea that an animal responds to a threat by preparing to stand and fight or run away. The nature of this response was thoroughly explained in a book on the physiology of pain, hunger, fear, and rage.

When students learn about the sympathetic system and the fight-or-flight response, they often stop and wonder about other responses. If you were faced with a lioness running toward you as pictured at the beginning of this chapter, would you run or would you stand your ground? Some people would say that they would freeze and not know what to do. So isn’t there really more to what the autonomic system does than fight, flight, rest, or digest. What about fear and paralysis in the face of a threat?

The common epithet of “fight or flight” is being enlarged to be “fight, flight, or fright” or even “fight, flight, fright, or freeze.” Cannon’s original contribution was a catchy phrase to express some of what the nervous system does in response to a threat, but it is incomplete. The sympathetic system is responsible for the physiological responses to emotional states. The name “sympathetic” can be said to mean that (sym- = “together” -pathos = “pain,” “suffering,” or “emotion”).

Interactive Link

Watch this video to learn more about the nervous system. As described in this video, the nervous system has a way to deal with threats and stress that is separate from the conscious control of the somatic nervous system. The system comes from a time when threats were about survival, but in the modern age, these responses become part of stress and anxiety. This video describes how the autonomic system is only part of the response to threats, or stressors. What other organ system gets involved, and what part of the brain coordinates the two systems for the entire response, including epinephrine (adrenaline) and cortisol?


The accelerans, or sympathetic nerves, carry nerve impulses from the medulla oblongata in the brain to the heart. The heart responds by increasing both the rate of contraction and the strength of the contractions. Exercise is one way that this pathway is activated, and can increase your heart rate to up to 180 beats per minute. This will increase the amount of blood pumped by the heart and sent out to exercising muscles.

When you exercise, your cells use up more oxygen and more carbon dioxide is produced. The increased concentration of carbon dioxide is recorded by special receptors in the aorta and carotid arteries, and this information is passed to the medulla oblongata. Another effect of exercise is that the muscle pump works harder. The muscle pump is the contraction of muscles surrounding your veins, which pushes blood back to the heart. The harder the muscle pump works, the more blood gets sent to the right atrium of the heart. As the atrium stretches to accommodate the extra blood, the stretch receptors in the heart muscle relay the information to the medulla oblongata. These two sources of information will cause the activation of the pathway that will increase your heart rate, thus relieving the full atrium and moving excess carbon dioxide to the lungs for expulsion from the body.


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@shell4life – I believe that panic attacks are brought on by nervousness. It can either be anxiety that you've been dealing with for awhile or a sudden situation that makes you feel fear.

Once your nerves start reacting to the anxiety, it becomes hard to breathe. You may hyperventilate, and you may feel like you are about to pass out.

I used to have panic attacks, and I would feel as if I were falling out of reality. I had to put my head between my knees and breathe deeply, and this seemed to counteract the nerves that were making me hyperventilate. shell4life February 8, 2013

How do the nervous system and the respiratory system come into play when a person is having a panic attack? I had my first one last week, and I felt both nervous and out of breath. StarJo February 7, 2013

@seag47 – It's probably the same thing that happens when you hold your breath for too long and you feel the overwhelming urge to breath. I've had to hold my breath in an MRI before, and after about thirty seconds, I had to start letting some of the air out and taking in short breaths to survive, because I just could not keep it in any longer. seag47 February 7, 2013

I've definitely gotten the signal to slow down while running before. I get out of breath really easily, so any time that I run for even a short distance, my chest starts to hurt, and I have to stop.

I never really thought about my nervous system getting in on this. I always just assumed that the reason I stopped was because I couldn't catch my breath, but it was also because my nerves told my brain that I needed to stop.


How Does the Human Body Maintain Homeostasis?

The human body is an exquisite machine, partly because it maintains functionality in a variety of environments. Humans can thrive in conditions ranging from the arctic to the equator, and with a variety of diets and lifestyles. Part of the reason for this adaptability is the body’s ability to maintain homeostasis.

Homeostasis is a fancy word meaning "equilibrium," and it entails many interwoven variables that are amazing to consider. Temperature is among the most straightforward of these. The body sweats to keep cool and shivers to stay warm. But the human body is masterful at balancing many other factors. Most are subtler, involving the regulation of hormones and other bodily chemicals. All of the body’s systems self-regulate using an intricate coordination of three principle roles: signal reception, centralized control and action.

All of the body’s systems work together to maintain balance in the body, but various systems do have specific roles. Two of the most important systems for maintaining homeostasis are the nervous and endocrine systems. Basic bodily functions such as heart rate and breathing may be stimulated or slowed under neural control. The nervous system helps regulate breathing and the urinary and digestive systems, and it interacts with the endocrine system. For example, part of the brain triggers the pituitary gland to release metabolic hormones in response to changing caloric demands. Hormones also help adjust the body’s balance of fluids and electrolytes, among other key roles in all the body’s systems. Less energetically expensive, but no less important, roles in the maintenance of homeostasis include the lymphatic system’s ability to fight infection, the respiratory system’s maintenance of oxygen and proper pH levels, and the urinary system’s removal of toxins from the blood.

The human body fends off many challenges to its maintenance of balance. A diet that lacks the right nutrients in the right amounts will induce the body to compensate or become sick. Exposure to drugs, alcohol and other toxins kick the excretory functions into high gear, lest these substances accumulate and damage the body’s cells. Stress and depression can challenge the respiratory, cardiovascular and endocrine systems, and thereby weaken their respective abilities to maintain homeostasis. And insufficient sleep can work all of the body’s systems too hard, impairing the body’s balance. So, while the human body is an amazing entity with exquisite abilities to counterbalance insults, healthy lifestyles and choices can go a long way to help.


High blood pressure is a &ldquosilent killer&rdquo

You may not feel that anything is wrong, but high blood pressure could be quietly causing damage that can threaten your health. The best prevention is knowing your numbers and making changes that matter in order to prevent and manage high blood pressure.

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Written by American Heart Association editorial staff and reviewed by science and medicine advisers. See our editorial policies and staff.


Watch the video: Ο ανθρώπινος εγκέφαλος αποκαλύπτει τα μυστικά.. - futuris (July 2022).


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