What are endorphins

Endorphins is made up of two descriptive terms, endogenous and morphine, which are opioid neuropeptides which are naturally produced in your body that serve a primary function as an agent blocking the perception of pain and additionally, present in cases of pleasure ¹. Historically, morphine receptors were discovered in the nervous system before the discovery and understanding of endorphins.

Endorphins were discovered to not only display functions as neurotransmitters in the central nervous system (brain and spinal cord) but additionally as peptide hormones released into the circulatory system by the pituitary gland ¹. Endorphins have been linked clinically to cases of mental issues including autism, depression, and depersonalization disorder as well as to activities such as laughter and vigorous aerobic exercise ¹.

The origins of endorphins have been traced to the precursor pro-opiomelanocortin (POMC) polypeptide which is synthesized in the pituitary gland. Recent studies have produced evidence suggesting that pro-opiomelanocortin (POMC) may also be produced by the immune system ¹ and consequently, also provide a base source for endorphin production. Pro-opiomelanocortin (POMC) consists of a 241 amino acid chain which is cleaved by enzyme (prohormone convertases) action into the 93 amino acid single chain polypeptide beta-lipoprotein (beta-LPH). Beta-LPH is cleaved via enzymes into beta-melanocyte-stimulating hormone and endorphins, amongst other molecule types.

Beta-endorphins are proteins that are primarily synthesized by the anterior pituitary gland in response to physiologic stressors such as pain ². Beta-endorphins function through various mechanisms in both the central and peripheral nervous system to relieve pain when bound to their mu-opioid receptors. Opioid medications function by mimicking natural endorphins, competing for receptor binding. In the acute setting, exogenous opiates inhibit the production of endogenous opiates while in the chronic setting, exogenous opiates inhibit the production of both endogenous opiates and mu-opioid receptors. Risks associated with chronic opiate use include opioid induced hyperalgesia, tolerance and addiction. In the future, we hope to understand the dynamics between beta-endorphins and non-opioid pain medications to offer patients maximal pain management with minimal associated risk.

Types of endorphins

Endorphins are identified as three distinct peptides termed alpha-endorphins, beta-endorphins, and gamma-endorphins. The beta-endorphins are the longest chain, containing 31 amino acids in the following sequence: Tyr-Gly-Gly-Phe-Met-Thr-Ser-Glu-Lys-Ser-Gln-Thr-Pro-Leu-Val-Thr-Leu-Phe-Lys-Asn-Ala-Ile-Ile-Lys-Asn-Ala-Tyr-Lys-Lys-Gly-Glu. This sequence corresponds to amino acids 104 to 134 in the sequence of beta-LPH. The second longest chain is the gamma-endorphins, consisting of a 17 amino acid chain the same as the first 17 amino acid chain sequence of the beta-endorphins. Finally, the third and shortest type of endorphins about the amino acid chain sequence are the alpha-endorphins. The alpha-endorphins are amino acid chains comprised of the same first 16 amino acid sequence as the beta-endorphins (and consequently has the same sequence of the first 16 amino acids comprising the gamma-endorphins). Thus, the sequences of beta-endorphins and gamma-endorphins essentially have the sequence of alpha-endorphins nested within them. This molecular configuration thereby allows these endorphins to be the agonist of opioid receptors, the same receptors to which chemicals derived from opium, such as morphine, bind to for triggering physiological responses.

Alpha-endorphins are endogenous opioid peptides derived from beta-endorphins of the pro-opiomelanocortin (POMC) system. Alpha-endorphin is the 16-amino acid sequence of the N-terminal of beta-endorphin and differs from gamma-endorphin by one amino acid (beta-endorphin 1-17).

Gamma-endorphins are endogenous opioid peptides derived from beta-lipotropin of the pro-opiomelanocortin (POMC) system. Gamma-endorphin is the 17-amino acid sequence of the N-terminal of beta-endorphin and differs from alpha-endorphin by one amino acid (beta-endorphin 1-16).

Where are endorphins produced?

Beta-endorphins are primarily synthesized and stored in the anterior pituitary gland ³ from their precursor protein pro-opiomelanocortin (POMC). However, recent studies suggest cells of the immune system are also capable of beta-endorphin synthesis because immune cells possess mRNA transcripts for POMC ⁴ and T-lymphocytes, B-lymphocytes, monocytes and macrophages have been shown to contain endorphins during inflammation ⁵.

Pro-opiomelanocortin (POMC) is a large protein that is cleaved into smaller proteins such as beta-endorphin, alpha-melanocyte stimulating hormone (MSH), adrenocorticotropin (ACTH), and others. The pituitary gland synthesizes POMC in response to a signal from the hypothalamus; that signal being corticotroponin-releasing hormone (CRH). The hypothalamus releases corticotroponin-releasing hormone in response to physiologic stressors such as pain, as in the postoperative period. When the protein products of POMC cleavage accumulate in excess, they turn hypothalamic corticotroponin-releasing hormone production off – that is, feedback inhibition occurs ⁶.

Endorphins function

The function of endorphins can be stated in general terms as well as broken down specifically and observed per each endorphin type. In general, the release of endorphins is understood to be associated with the body’s response to pain and also exercise as associated with “runner’s high” ¹. The pain relief experienced as a result of the release of endorphins has been determined to be greater than that of morphine. Additionally, endorphins have been found to be associated with states of pleasure including such emotions brought upon by laughter, love, sex, and even appetizing food ¹. Of the three endorphin types, beta-endorphins have been the most studied and prevalent, accounting for the majority of the functional properties of endorphins as generalized and understood as a whole. Research is ongoing on each type to further understand the full functional potential of each along with how they can be used in a medically beneficial manner. Endorphins express functional duality as they fall into the category of either neurotransmitters or neuromodulators in the central nervous system (CNS) and hormones in the pituitary gland.

The mechanism of endorphins can be viewed through two different lenses through activity in the peripheral nervous system (PNS) and the central nervous system (CNS). In the peripheral nervous system, the perception of pain relief is produced beta-endorphins bind to opioid receptors ¹. Opioid receptors are broken down into four primary classes of G protein-coupled receptors: mu-receptors, delta-receptors, kappa-receptors, and nociceptin receptors. The greatest binding potential exists between the beta-endorphins and the mu-receptors. Mu-receptors can be found throughout nerves of the peripheral nervous system. When this beta-endorphin to mu-receptor binding occurs on nerve terminals (happening pre-synaptically or post-synaptically), analgesic effects are realized. The effects are realized as the aforementioned binding results in a triggering of chemical events preventing the release of substance P, amongst other tachykinins, which is an instrumental undecapeptide in the conveyance of pain. Just as beta-endorphin to mu-opioid binding occurs in the peripheral nervous system, it also occurs in the central nervous system. There is a difference though, as the mechanism triggered by the binding opposes the release of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) as opposed to substance P. With this suppression of GABA, the result is an increase in production and action of dopamine, the pleasure, and reward-associated neurotransmitter.

What do endorphins do?

From a clinical standpoint, endorphins and their effects and interactions are still being understood and studied ¹.

In the peripheral nervous system (PNS), beta-endorphins produce analgesia by binding to opioid receptors (particularly of the mu subtype) at both pre- and post- synaptic nerve terminals, primarily exerting their effect through presynaptic binding ². When bound, a cascade of interactions results in inhibition of the release of tachykinins, particularly substance P, a key protein involved in the transmission of pain ⁷. In the peripheral nervous system, mu-opioid receptors are present throughout peripheral nerves and have been identified in the central terminals of primary afferent neurons, peripheral sensory nerve fibers and dorsal root ganglia ⁸.

In the central nervous system, beta-endorphins similarly bind mu-opioid receptors and exert their primary action at presynaptic nerve terminals. However, instead of inhibiting substance P, they exert their analgesic effect by inhibiting the release of GABA, an inhibitory neurotransmitter, resulting in excess production of dopamine ⁷. Dopamine is associated with pleasure. In the CNS, mu-opioid receptors are most abundant in descending pain control circuits including the amygdala, mesencephalic reticular formation, periaqueductal gray matter (PAG) and rostral ventral medulla ⁹.

One basic yet noteworthy interaction of endorphins is with naloxone. Naloxone is administered as a drug, typically in the case of opioid overdose to mitigate bodily response to the opioid. This is achieved by binding to the opioid receptors, making it not only difficult for opioid binding but also endorphin binding, and thereby reducing the effect of available endorphins. Studies have been conducted in relation to naloxone usage in the presence of depersonalization disorder, and it was found that patient conditions improved. Based on this, endorphins are suspected of being linked with contributing to this disorder. Another interaction of clinical significance includes cases where the patient has a physical dependence to an opiate. Links have been made to opiate dependence and hypothalamo-hypophyseal-gonadal dysfunction. Studies have supported beta-endorphins as affecting the pituitary gland’s release of luteinizing hormone through gonadotropin-releasing hormone influence and thereby as being involved with gonadal homeostasis. Thus, the association is made between the effects of opiate dependency on gonadal homeostasis via the interruption of effective beta-endorphin action. An interesting correlation also has been made about the administration of opioid medications versus non-opioid pain medication prescribed for patients following surgery. Levels of beta-endorphins were found to be high in patients using the opioid medications, correlating to a physiological response to pain. However, it was interesting to note that in the presence of rofecoxib (a COX-2 inhibitor), beta-endorphin levels remain unaffected as opposed to in the presence of acetaminophen, where beta-endorphin levels declined with its use. The rofecoxib resulted in a less perceived feeling of pain, potentially attributed to the maintenance of the beta-endorphin levels, but exactly in what way this interaction allowed for this is still being understood. The result of such deeper understanding would be to exploit that knowledge to use more effective non-opioid pain reducers that lack the negative properties of opioids such as addiction and tolerance over prolonged usage.

Role of Beta-Endorphins in Surgery

Opioid medications (e.g. Vicodin, Morphine, Fentanyl) are commonly prescribed in the postoperative period. These medications exert their effect by mimicking natural endorphins, binding to mu-opioid receptors in both the central nervous system (CNS) and peripheral nervous system (PNS) with variable specificity. This is accomplished by sharing a beta-phenylethylamine group, the moiety that binds the opioid receptor ¹⁰.

Acute administration of exogenous opioids inhibits the production of endogenous opiates (e.g. beta-endorphins). Patients undergoing general anesthesia have shown a significant increase in beta-endorphins during surgery. This increase was effectively inhibited by the co-administration of fentanyl ¹¹. In similar studies, Hargreaves et al. ¹² showed that patients who underwent dental surgery and were given local anesthetic (lidocaine) alone had increased plasma beta-endorphin levels during and after surgery. However, when fentanyl was co administered, plasma beta-endorphin levels were significantly reduced. Of note, patients reported less pain during the surgery when the fentanyl was co-administered.

Chronic administration of exogenous opioids inhibits the production of both endogenous opiates and mu-opioid receptors. Multiple studies have demonstrated the down regulation of POMC gene expression and subsequent decrease in endorphin production in rats given chronic morphine ¹³. And Zhang et al. ¹⁴ found that mu-opioid receptors on beta-endorphin containing neurons of the hypothalamus of guinea pigs decreased in density after chronic-morphine treatment. Furthermore, Christie et al. ¹⁵ found that exogenous opioids, such as morphine, cause an uncoupling of mu-opioid receptors from their ligand-gated voltage channel with a decrease in both potency and efficacy of the channel.

Surgical patients occasionally require treatment for pain over an extended period of time. However, chronic administration of opioid analgesics carries significant risks of opioid induced hyperalgesia, tolerance and addiction. Reports as early as the 19th century reveal patients who experienced hyperalgesia (increased sensitivity to painful stimuli) and allodynia (pain elicited from a normally nonpainful stimulus) upon the cessation of morphine use ¹⁶. While down regulation of both endorphins and mu receptors associated with chronic exogenous opioid use likely play a role in opioid induced hyperalgesia, antiopioid peptides are also likely involved. The anti-opioid peptides described thus far include cholecystokinin (CCK), neuropeptide FF (NPFF) and orphanin FQ/nociceptin. These anti-opioid peptides are thought to exert their action by binding mu receptors thereby decreasing their affinity for endorphins and similar opioids ¹⁷. Both the down regulation of endorphins and mu receptors, as well as the production of anti-opioid peptides, are processes that occur over time. As these processes occur, patients require increasing amounts of opioids to induce the same level of analgesia, a process known as tolerance ¹⁸. Addiction is described as a brain disease resulting in a loss of control over drug taking or in compulsive drug seeking, despite noxious consequences ¹⁹. While the aforementioned mechanisms associated with opioid induced hyperalgesia and tolerance are likely key contributors to opioid addiction, a discussion of addiction would not be complete without briefly discussing the association between the dopaminergic reward system and opiates. Opioids in the CNS exert their analgesic effect by increasing dopamine release by disinhibiting GABA’s effect on dopaminergic neurons. The dopaminergic neurons most associated with addiction are those of the “reward center” including the ventral tegmental area, nucleus accumbens system, prefrontal cortex and extended amygdala ¹³. To maintain normal dopamine levels, patients who develop tolerance require increased amounts of exogenous opioids. Conversely, when the patient who is reliant on exogenous opioids to maintain dopamine homeostasis attempts to cease opioid use, they frequently suffer severe withdrawal symptoms and may employ drug-seeking behavior.

The degree of pain experienced by the surgical patient during and after a procedure correlates with plasma beta-endorphin level. A study of pre- and postoperative beta-endorphin levels was conducted for various major surgeries. It was found that both pre- and postoperative plasma beta-endorphin levels correlated positively with postoperative pain severity ²⁰. In a similar study comparing plasma beta-endorphin levels between open- and laparoscopic cholecystectomies, an invasive and minimally invasive procedure respectively, Le Blanc et al. ²¹ concluded that endorphins are most likely excreted in response to postoperative pain. Earlier studies have also found a negative correlation between intra-operative plasma beta-endorphin concentration and postoperative pain severity ²².

Non-opioid medications affect plasma beta-endorphin levels through unknown mechanisms. In a study of osteoarthritis of the knee, both acetaminophen and rofecoxib (a COX-2 inhibitor) were administered to patients with symptomatic osteoarthritis. Rofecoxib produced significantly better analgesia than acetaminophen, reducing pain intensity by 56% and 29%, respectively. However, plasma beta-endorphin levels were unaffected in the rofecoxib group but declined significantly in the acetaminophen group ²³, suggesting either rofecoxib supports beta-endorphin synthesis, durability or both or acetaminophen inhibits it. Additionally, Parsa et al. ²⁴ demonstrated decreased postoperative pain severity and opioid requirements following preoperative administration of celecoxib plus gabapentin. In the future, more research may reveal the dynamics between beta-endorphins and other non-opioid medications to provide more effective analgesia without the risks associated with opioid medications.

How to release endorphins?

In general, the release of endorphins is understood to be associated with the body’s response to pain and also exercise as associated with “runner’s high” ¹. This is a sensation of euphoria that has been attributed to the central effects of endorphins and other endogenous opioids, seen as responsible for whether or not dependences or addictive behaviors appear ²⁵. Many practitioners of physical exercise, especially runners, commonly experience these neurobiological rewards, during and after distance running ²⁶. Endorphins produced by the body are converted in their own opiate-like peptides, which can cause dependence (and consequently may be the route of withdrawal symptoms ²⁷. Because beta-endorphin is secreted and modify its levels during vigorous exercise ²⁸, different studies have examined the effects of exercise intensity on endogenous opioid production during cycling, running on a treadmill and running marathons ²⁷. Sensations experienced have been described as a state of sheer joy, euphoria, inner harmony, limitless energy, feelings of wellbeing and a reduced perception of pain ²⁹. Such emotions and sensations very similar to those described by drug addicts and people addicted to other types of substances ³⁰. The connection between beta-endorphins and runner’s high is a suitable explanation for exercise addiction in endurance activities, although more empirical support is still required ²⁷.

Some studies suggest that exercise increases beta-endorphin levels, provides pain relief during labor ³¹ and reduces the need for epidural analgesia ³². However the results of studies on reduced pain perception ³³ due to increased levels of beta-endorphins at the time of delivery are inconclusive ³⁴.

Endorphins and exercise

Regular physical exercise is an activity with a major capacity to maintain and improve physical and mental health ³⁵. Nonetheless, in the light of the results of research, excessive practicing may cause serious health problems, giving rise to the appearance of addictive behaviors ³⁶. Many models have attempted to explain this behavior. However, the idea underlying most of them is that exercise has the power to constitute a positive reinforcement, besides its ability to act as a stress-reduction strategy ³⁷. In turn, it has been noted that the genes which control a liking for drugs are also responsible for naturally gratifying behaviors like exercise ³⁷. It is at this point that running and endurance sports have a differentiating role, being seen as types with an antidepressant capacity which have the potential to reduce psychological distress through pleasure induction by activating endogenous opiates ³⁶. This is borne out by the number of endurance athletes who state that they started practicing this sport as a way of beating some other addiction, or as a means of reducing stress. Nevertheless, in many instances their strong dedication and the immediate gratification received turns them into exercise addicts ³⁸. For their part, Antunes et al. ²⁶ demonstrated that deprivation of exercise for 2 weeks caused a decline in feelings of well-being, with detection of low levels of anandamide endocannabinoids and an increase in the levels of beta-endorphins.

The results of research on participants in endurance sports give evidence for a relationship between exercise commitment and exercise dependence ³⁹. This is due to the heavy demands ⁴⁰ and considerable number of hours and sessions given over to training ⁴¹. Examples are the triathletes studied by Youngman and Simpson ⁴², or the marathon runners investigated by Karr et al. ⁴³ and Zarauz-Sancho et al. ⁴⁴, these authors finding a positive correlation between the total hours spent training and the risk of addiction to exercise.

Other variables taken into account are sex and age. With regard to the latter, most research has detected no significant differences by age ³⁵. Although an early study on a small group of marathon racers found that women scored significantly higher in exercise dependence than men ⁴⁵, there are no other reports of sex differences in exercise addiction among runners, in spite of differences in motives for participation; women usually run more because of a preoccupation with controlling weight and body image, whilst men do so because of the impact of a social and competitive nature that practicing this sport provides ⁴⁶. For their part, Buning and Walker ⁴⁷, Rundio et al. ⁴⁸, and Schüler et al. ⁴⁹ demonstrated that runners’ motivation differs according to the characteristics of the event, attracting them as a function of the degree to which their essential motives are fulfilled and their basic needs met.

In recent years, research has attempted to seek out the relationship between addiction to exercise and other factors such as passion ⁵⁰, considering this to be a useful tool for appropriate training and for supervising the well-being of athletes ⁵¹, and Kovacsik et al. ⁵² have shown a relationship between the risk for exercise addiction, exercise intensity and passion. Lane and Wilson ⁵³ found that runners underwent significant changes in their emotions during runs, besides demonstrating that emotional intelligence correlates with pleasant feelings in the course of such events. More recently, Rivera Rodríguez et al. ⁵⁴ have described long-distance running is beneficial when it comes to completing tasks that require keeping cognitive effort at a high level of vigilance, selective attention, decision-making, cognitive control, self-regulation and motor behaviors.

A recent piece of research undertaken by Martin et al. ⁵⁵ has highlighted the fact that people practicing endurance sports continue despite being injured and in addition have high scores on the Inventory of Addiction to Exercise. The practitioners of endurance sports studied pressed on in spite of the negative consequences brought about by not running in the best physical condition, because the recompense they derive is greater than any reward from not doing so. Competitive runners show a greater number of symptoms of addiction when compared to non-competitive, regardless of their sex ⁵⁶. In any case, effort in future research in this field should be focused on conceptualizing, delimiting, unifying and studying the role of various different factors in the development of addiction to exercise ⁵⁷. The aim should be an attempt to guide or divert sports activities in the direction of health ⁵⁶.

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