Endorphin
Encyclopedia
Endorphins are endogenous
Endogenous
Endogenous substances are those that originate from within an organism, tissue, or cell. Endogenous retroviruses are caused by ancient infections of germ cells in humans, mammals and other vertebrates...

 opioid
Opioid
An opioid is a psychoactive chemical that works by binding to opioid receptors, which are found principally in the central and peripheral nervous system and the gastrointestinal tract...

 peptide
Peptide
Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...

s that function as neurotransmitters. They are produced by the pituitary gland
Pituitary gland
In vertebrate anatomy the pituitary gland, or hypophysis, is an endocrine gland about the size of a pea and weighing 0.5 g , in humans. It is a protrusion off the bottom of the hypothalamus at the base of the brain, and rests in a small, bony cavity covered by a dural fold...

 and the hypothalamus
Hypothalamus
The Hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions...

 in vertebrate
Vertebrate
Vertebrates are animals that are members of the subphylum Vertebrata . Vertebrates are the largest group of chordates, with currently about 58,000 species described. Vertebrates include the jawless fishes, bony fishes, sharks and rays, amphibians, reptiles, mammals, and birds...

s during exercise, excitement
Excited state
Excitation is an elevation in energy level above an arbitrary baseline energy state. In physics there is a specific technical definition for energy level which is often associated with an atom being excited to an excited state....

, pain
Pain
Pain is an unpleasant sensation often caused by intense or damaging stimuli such as stubbing a toe, burning a finger, putting iodine on a cut, and bumping the "funny bone."...

, consumption of spicy food
Capsaicin
Capsaicin 2CHCH=CH4CONHCH2C6H3-4--3- ) is the active component of chili peppers, which are plants belonging to the genus Capsicum. It is an irritant for mammals, including humans, and produces a sensation of burning in any tissue with which it comes into contact...

, love
Love
Love is an emotion of strong affection and personal attachment. In philosophical context, love is a virtue representing all of human kindness, compassion, and affection. Love is central to many religions, as in the Christian phrase, "God is love" or Agape in the Canonical gospels...

 and orgasm
Orgasm
Orgasm is the peak of the plateau phase of the sexual response cycle, characterized by an intense sensation of pleasure...

, and they resemble the opiate
Opiate
In medicine, the term opiate describes any of the narcotic opioid alkaloids found as natural products in the opium poppy plant.-Overview:Opiates are so named because they are constituents or derivatives of constituents found in opium, which is processed from the latex sap of the opium poppy,...

s in their abilities to produce analgesia and a feeling of well-being.

The term endorphin implies a pharmacological
Pharmacology
Pharmacology is the branch of medicine and biology concerned with the study of drug action. More specifically, it is the study of the interactions that occur between a living organism and chemicals that affect normal or abnormal biochemical function...

 activity (analogous to the activity of the corticosteroid
Corticosteroid
Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex. Corticosteroids are involved in a wide range of physiologic systems such as stress response, immune response and regulation of inflammation, carbohydrate metabolism, protein catabolism, blood electrolyte...

 category of biochemicals) as opposed to a specific chemical formulation. It consists of two parts: endo- and -orphin; these are short forms of the words endogenous and morphine, intended to mean "a morphine-like substance originating from within the body."

The term endorphin rush has been adopted in popular speech to refer to feelings of exhilaration brought on by pain, danger, or other forms of stress, supposedly due to the influence of endorphins. When a nerve impulse reaches the spinal cord, endorphins that prevent nerve cells from releasing more pain signals are released. Immediately after injury, endorphins allow animals to feel a sense of power and control over themselves that allows them to persist with activity for an extended time.

History

Opioid neuropeptides
Opioid peptide
Opioid peptides are short sequences of amino acids that bind to opioid receptors in the brain; opiates and opioids mimic the effect of these peptides. Opioid peptides may be produced by the body itself, for example endorphins. The effects of these peptides vary, but they all resemble opiates...

 were first discovered in 1974 by two independent groups of investigators:
  • John Hughes and Hans Kosterlitz of Scotland
    Scotland
    Scotland is a country that is part of the United Kingdom. Occupying the northern third of the island of Great Britain, it shares a border with England to the south and is bounded by the North Sea to the east, the Atlantic Ocean to the north and west, and the North Channel and Irish Sea to the...

     isolated — from the brain
    Brain
    The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...

     of a pig
    Pig
    A pig is any of the animals in the genus Sus, within the Suidae family of even-toed ungulates. Pigs include the domestic pig, its ancestor the wild boar, and several other wild relatives...

     — what they called enkephalin
    Enkephalin
    An enkephalin is a pentapeptide involved in regulating nociception in the body. The enkephalins are termed endogenous ligands, or specifically endorphins, as they are internally derived and bind to the body's opioid receptors. Discovered in 1975, two forms of enkephalin were revealed, one...

    s (from the Greek
    Greek language
    Greek is an independent branch of the Indo-European family of languages. Native to the southern Balkans, it has the longest documented history of any Indo-European language, spanning 34 centuries of written records. Its writing system has been the Greek alphabet for the majority of its history;...

     , ).

  • Around the same time, in the calf
    Calf
    Calves are the young of domestic cattle. Calves are reared to become adult cattle, or are slaughtered for their meat, called veal.-Terminology:...

     brain, Rabi Simantov and Solomon H. Snyder
    Solomon H. Snyder
    Solomon H. Snyder is an American neuroscientist.Snyder attended Georgetown University 1955-1958 and received his MD from Georgetown University School of Medicine in 1962. After medical internship at the Kaiser Hospital in San Francisco, he served as a research associate 1963-1965 at the NIH,...

     of the United States
    United States
    The United States of America is a federal constitutional republic comprising fifty states and a federal district...

     found what Eric Simon (who independently discovered opioid receptors in the brain) later termed "endorphin" by an abbreviation
    Abbreviation
    An abbreviation is a shortened form of a word or phrase. Usually, but not always, it consists of a letter or group of letters taken from the word or phrase...

     of "endogenous morphine", meaning "morphine
    Morphine
    Morphine is a potent opiate analgesic medication and is considered to be the prototypical opioid. It was first isolated in 1804 by Friedrich Sertürner, first distributed by same in 1817, and first commercially sold by Merck in 1827, which at the time was a single small chemists' shop. It was more...

     produced naturally in the body". Importantly, recent studies have demonstrated that diverse animal and human tissues are in fact capable of producing morphine itself, which is not a peptide
    Peptide
    Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...

    .

Mechanism of action

β-Endorphin
Beta-endorphin
β-endorphin is an endogenous opioid peptide neurotransmitter found in the neurons of both the central and peripheral nervous system.The amino acid sequence is:...

 is released into blood from the pituitary gland
Pituitary gland
In vertebrate anatomy the pituitary gland, or hypophysis, is an endocrine gland about the size of a pea and weighing 0.5 g , in humans. It is a protrusion off the bottom of the hypothalamus at the base of the brain, and rests in a small, bony cavity covered by a dural fold...

 and into the spinal cord
Spinal cord
The spinal cord is a long, thin, tubular bundle of nervous tissue and support cells that extends from the brain . The brain and spinal cord together make up the central nervous system...

 and brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...

 from hypothalamic neurons. The β-endorphin that is released into the blood cannot enter the brain in large quantities because of the blood-brain barrier
Blood-brain barrier
The blood–brain barrier is a separation of circulating blood and the brain extracellular fluid in the central nervous system . It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion...

, so the physiological importance of the β-endorphin that can be measured in the blood is far from clear. β-Endorphin is a cleavage product of pro-opiomelanocortin (POMC), which is also the precursor hormone for adrenocorticotrophic hormone (ACTH). The behavioural effects of β-endorphin are exerted by its actions in the brain and spinal cord, and it is presumed that the hypothalamic neurons are the major source of β-endorphin at these sites. In situations where the level of ACTH is increased (e.g., Cushing’s Syndrome), the level of endorphins also increases slightly.

β-Endorphin has the highest affinity for the μ1 opioid receptor
Opioid receptor
Opioid receptors are a group of G protein-coupled receptors with opioids as ligands. The endogenous opioids are dynorphins, enkephalins, endorphins, endomorphins and nociceptin. The opioid receptors are ~40% identical to somatostatin receptors...

, slightly lower affinity for the μ2 and δ opioid receptors, and low affinity for the κ1 opioid receptors. μ-Opioid receptors are the main receptor through which morphine
Morphine
Morphine is a potent opiate analgesic medication and is considered to be the prototypical opioid. It was first isolated in 1804 by Friedrich Sertürner, first distributed by same in 1817, and first commercially sold by Merck in 1827, which at the time was a single small chemists' shop. It was more...

 acts. In the classical sense, μ opioid receptors are presynaptic, and inhibit neurotransmitter release; through this mechanism, they inhibit the release of the inhibitory neurotransmitter GABA
Gabâ
Gabâ or gabaa, for the people in many parts of the Philippines), is the concept of a non-human and non-divine, imminent retribution. A sort of negative karma, it is generally seen as an evil effect on a person because of their wrongdoings or transgressions...

, and disinhibit the dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...

 pathways, causing more dopamine to be released. By hijacking this process, exogenous opioids cause inappropriate dopamine release, and lead to aberrant synaptic plasticity
Synaptic plasticity
In neuroscience, synaptic plasticity is the ability of the connection, or synapse, between two neurons to change in strength in response to either use or disuse of transmission over synaptic pathways. Plastic change also results from the alteration of the number of receptors located on a synapse...

, which causes dependency. Opioid receptors have many other and more important roles in the brain and periphery however, modulating pain, cardiac, gastric and vascular function as well as possibly panic and satiation, and receptors are often found at postsynaptic locations as well as presynaptically.

Activity

Scientists debate whether specific activities release measurable levels of endorphins. Much of the current data comes from animal models which may not be relevant to humans. The studies that do involve humans often measure endorphin plasma
Blood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...

 levels, which do not necessarily correlate with levels in the central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...

. Other studies use a blanket opioid
Opioid
An opioid is a psychoactive chemical that works by binding to opioid receptors, which are found principally in the central and peripheral nervous system and the gastrointestinal tract...

 antagonist
Receptor antagonist
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...

 (usually naloxone
Naloxone
Naloxone is an opioid antagonist drug developed by Sankyo in the 1960s. Naloxone is a drug used to counter the effects of opiate overdose, for example heroin or morphine overdose. Naloxone is specifically used to counteract life-threatening depression of the central nervous system and respiratory...

) to indirectly measure the release of endorphins by observing the changes that occur when any endorphin activity that might be present is blocked.

Runner's high

A publicized effect of endorphin production is the so-called "runner's high", which is said to occur when strenuous exercise takes a person over a threshold that activates endorphin production. Endorphins are released during long, continuous workouts, when the level of intensity is between moderate and high, and breathing is difficult. This also corresponds with the time that muscles use up their stored glycogen
Glycogen
Glycogen is a molecule that serves as the secondary long-term energy storage in animal and fungal cells, with the primary energy stores being held in adipose tissue...

. During a release of endorphins, the person may be exposed to bodily harm from strenuous bodily functions after going past his or her body's physical limit. This means that runners can keep running despite pain, continuously surpassing what they once considered to be their limit. Runner's high has also been know to create feeling of euphoria and happiness in persons experiencing its side effects.

Runner's high has been shown to have evolutionary roots and is proven to help with the survival of early humans. Runner's high benefits early humans and still some current African tribes by allowing humans to run for vast lengths without pain. Most early humans hunted and gathered for their food. This required them to cover vast distances hunting down their prey or foraging for their food. This caused them to develop conditions such as shin splints and stress fractures in their shin and feet bones. Without runner's high to negate the pain caused by running on bones with these conditions, early humans would not have been able to repeatedly cover these vast distances in search of their food and thus would have starved. Current African tribes make use of runner's high when conducting persistence hunting. Persistence hunting
Persistence hunting
Persistence hunting is a hunting technique in which hunters use a combination of running and tracking to pursue prey to the point of exhaustion. While humans can sweat to reduce body heat their quadruped prey would need to slow from a gallop to pant. Today, it is very rare and seen only in a few...

 is a method of hunting in which tribesman hunt an animal and track it for many miles, normally around 10 miles, eventually killing the animal due to exhaustion.

In 2008, researchers in Germany reported on the mechanisms that cause the runner's high. Using PET scans combined with recently available chemicals that reveal endorphins in the brain, they were able to compare runners’ brains before and after a run.

It is also suggested by many that endorphins are some of the many chemicals that contribute to runner's high; other candidates include epinephrine
Epinephrine
Epinephrine is a hormone and a neurotransmitter. It increases heart rate, constricts blood vessels, dilates air passages and participates in the fight-or-flight response of the sympathetic nervous system. In chemical terms, adrenaline is one of a group of monoamines called the catecholamines...

, serotonin
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...

, and dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...

.

Endocanabanoids
Endocannabinoid system
The endocannabinoid system refers to a group of neuromodulatory lipids and their receptors that are involved in a variety of physiological processes including appetite, pain-sensation, mood, and memory; it mediates the psychoactive effects of cannabis and, broadly speaking, includes:* The...

 are the chemical most likely responsible for causing runner's high if endorphins are proved to not cause runner's high. Endocanabanoids are the body's natural chemical that interacts with the same brain receptor responsible for causing the high associated with marijuana use. In tests by the Institute of Georgia it was shown that endocannabinoid receptors were necessary for cognitive improvements due to exercise to occur. It is also shown that the endocannabinoids are involved in the reward system of the body, controlling the rewards for both exercise and consuming dessert. Another experiment that supports the endocannabinoid theory is that when mice were bred without the endocannabinoid receptor they ran thirty to forty percent less than regular mice. The only issue with the endocannabinoid theory is that it shows motivation and reward for running more than mood change, not eliminating it from the discussion of causes of runner’s high, but does not place it in the frontrunner position for causation.

Another theory for the cause of runners high is that runner’s high is simply a trance caused by overtaxing of the brain’s information processing power. An example of this is that runner’s high has been described as pure happiness, elation, feelings of unity with one’s self and/or nature, endless peacefulness, timelessness, inner harmony, boundless energy, as well as the reduction of pain sensations. These subjective descriptions are similar to the claims of distorted perception, atypical thought patterns, diminished awareness of one’s surroundings, and intensified introspective understanding of one’s sense of identity and emotional status made by people who describe trance states. This shows that runner’s high is an actual altered state of consciousness because it shares many similar characteristics with other altered states of consciousness. The overtaxing of the brain’s information processing power creates an altered state of consciousness that is out of touch and distracted, but while this does support the theory behind runner’s high being an altered state of consciousness, it does not explain the feelings of joy and happiness that are associated with symptoms of runner's high. This eliminates it from being a primary cause of runner’s high but it still may assist in the overall cause of runner's high.

Previous research on the role of endorphins in producing runner's high questioned the mechanisms at work, their data possibly demonstrated that the "high" comes from completing a challenge rather than as a result of exertion. Studies in the early 1980s cast doubt on the relationship between endorphins and the runner's high for several reasons:
  • The first was that when an antagonist (pharmacological agent that blocks the action for the substance under study) was infused (e.g., naloxone
    Naloxone
    Naloxone is an opioid antagonist drug developed by Sankyo in the 1960s. Naloxone is a drug used to counter the effects of opiate overdose, for example heroin or morphine overdose. Naloxone is specifically used to counteract life-threatening depression of the central nervous system and respiratory...

    ) or ingested (naltrexone
    Naltrexone
    Naltrexone is an opioid receptor antagonist used primarily in the management of alcohol dependence and opioid dependence. It is marketed in generic form as its hydrochloride salt, naltrexone hydrochloride, and marketed under the trade names Revia and Depade...

    ) the same changes in mood state occurred as when the person exercised with no blocker.

  • A study in 2003 by the Georgia Institute of Technology found that runner's high might be caused by the release of another naturally produced chemical, anandamide
    Anandamide
    Anandamide, also known as N-arachidonoylethanolamide or AEA, is an endogenous cannabinoid neurotransmitter. The name is taken from the Sanskrit word ananda, which means "bliss, delight", and amide. It is synthesized from N-arachidonoyl phosphatidylethanolamine by multiple pathways...

    . The authors suggest that the body produces this chemical to deal with prolonged stress and pain from strenuous exercise, similar to the original theory involving endorphins. However, the release of anandamide was not reported with the cognitive effects of the runner's high; this suggests that anandamide release may not be significantly related to runner's high.


Runner’s high is a phenomenon that was vital to our very survival back in primitive times, and is still crucial to the survival of some and the enjoyment in recreational running. While there are many theories as to what is the cause of the phenomenon, endorphins have the most decisive evidence to support it being the cause. Endocannabinoids are a likely cause as to the motivation behind why we run but not why runner’s high occurs. Even though endorphins are the most probable individual cause of runner’s high, it is more likely a cocktail of chemicals reacting in the brain along with the overtaxing of the brain’s information processing capabilities which produces the phenomenon known as runner’s high.

Depersonalization disorder

Endorphins are known to play a role in depersonalization disorder
Depersonalization disorder
Depersonalization disorder is a dissociative disorder in which the sufferer is affected by persistent or recurrent feelings of depersonalization and/or derealization. Diagnostic criteria include persistent or recurrent experiences of feeling detached from one's mental processes or body...

. The opioid antagonists naloxone
Naloxone
Naloxone is an opioid antagonist drug developed by Sankyo in the 1960s. Naloxone is a drug used to counter the effects of opiate overdose, for example heroin or morphine overdose. Naloxone is specifically used to counteract life-threatening depression of the central nervous system and respiratory...

 and naltrexone
Naltrexone
Naltrexone is an opioid receptor antagonist used primarily in the management of alcohol dependence and opioid dependence. It is marketed in generic form as its hydrochloride salt, naltrexone hydrochloride, and marketed under the trade names Revia and Depade...

 have both been proven to be successful in treating depersonalization . To quote a 2001 naloxone study, "In three of 14 patients, depersonalization symptoms disappeared entirely and seven patients showed a marked improvement. The therapeutic effect of naloxone provides evidence for the role of the endogenous opioid system in the pathogenesis of depersonalization."

Relaxation

In 2003, clinical researchers reported that profound relaxation in a float tank
Isolation tank
An isolation tank is a lightless, soundproof tank inside which subjects float in salt water at skin temperature. They were first used by John C. Lilly in 1954 to test the effects of sensory deprivation. Such tanks are now also used for meditation and relaxation and in alternative medicine. The...

  triggers the production of endorphins. This explains the pain relief experienced during float sessions.

Acupuncture

In 1999, clinical researchers reported that inserting acupuncture
Acupuncture
Acupuncture is a type of alternative medicine that treats patients by insertion and manipulation of solid, generally thin needles in the body....

 needles into specific body points triggers the production of endorphins. In another study, higher levels of endorphins were found in cerebrospinal fluid
Cerebrospinal fluid
Cerebrospinal fluid , Liquor cerebrospinalis, is a clear, colorless, bodily fluid, that occupies the subarachnoid space and the ventricular system around and inside the brain and spinal cord...

 after patients underwent acupuncture. In addition, naloxone
Naloxone
Naloxone is an opioid antagonist drug developed by Sankyo in the 1960s. Naloxone is a drug used to counter the effects of opiate overdose, for example heroin or morphine overdose. Naloxone is specifically used to counteract life-threatening depression of the central nervous system and respiratory...

 appeared to block acupuncture’s pain-relieving effects.

Pregnancy

A placenta
Placenta
The placenta is an organ that connects the developing fetus to the uterine wall to allow nutrient uptake, waste elimination, and gas exchange via the mother's blood supply. "True" placentas are a defining characteristic of eutherian or "placental" mammals, but are also found in some snakes and...

l tissue of foetal origin — i.e., the syncytiotrophoblast
Syncytiotrophoblast
Syncytiotrophoblast is the epithelial covering of the placenta villous tree. It is a unique tissue in that it is a multi-nucleated, terminally differentiated syncytium, extending to 13m^2...

 — excretes beta-endorphins into the maternal blood system from the 3rd month of pregnancy. A recent study proposes an adaptive background for this phenomenon. The authors argue that fetuses make their mothers endorphin-dependent then manipulate them to increase nutrient allocation to the placenta. Their hypothesis predicts that: (1) anatomic position of endorphin production should mirror its presumed role in foetal-maternal conflict; (2) endorphin levels should co-vary positively with nutrient carrying capacity of maternal blood system; (3) postpartum psychological symptoms
Postpartum depression
Postpartum depression , also called postnatal depression, is a form of clinical depression which can affect women, and less frequently men, typically after childbirth. Studies report prevalence rates among women from 5% to 25%, but methodological differences among the studies make the actual...

 (such as postpartum blues, depression, and psychosis) in humans are side-effects of this mechanism that can be interpreted as endorphin-deprivation symptoms; (4) shortly after parturition, placentophagy
Placentophagy
Placentophagy is the act of mammals eating the placenta of their young after childbirth.The placenta contains high levels of prostaglandin which stimulates involution of the uterus, in effect cleaning the uterus out...

 could play an adaptive role in decreasing the negative side-effects of foetal manipulation; (5) later, breast-feeding-induced endorphin excretion of the maternal pituitary saves mother from further deprivation symptoms. These predictions appear to be supported by empirical data.

Etymology

From the meaning "within" (endogenous
Endogenous
Endogenous substances are those that originate from within an organism, tissue, or cell. Endogenous retroviruses are caused by ancient infections of germ cells in humans, mammals and other vertebrates...

, , "proceeding from within") and morphine
Morphine
Morphine is a potent opiate analgesic medication and is considered to be the prototypical opioid. It was first isolated in 1804 by Friedrich Sertürner, first distributed by same in 1817, and first commercially sold by Merck in 1827, which at the time was a single small chemists' shop. It was more...

, from Morpheus
Morpheus (mythology)
Morpheus in Greek mythology is the god of dreams, leader of the Oneiroi. Morpheus has the ability to take any human form and appear in dreams...

, , the god of dreams in the Greek mythology, thus 'endo(genous) (mo)rphine’.
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