Understanding Endorphins and Their Importance in Pain Management

Introduction

The purpose of this article is to briefly review our current understanding of endorphins, specifically beta-endorphins, and how they relate to the field of surgery. Beta-endorphins are neuropeptides involved in pain management, possessing morphine like effects, and are involved in natural reward circuits such as feeding, drinking, sex and maternal behavior.¹ Their application to the field of surgery centers on their role in pain management.

Synthesis, Storage and Secretion of Beta-Endorphins

Beta-endorphins are primarily synthesized and stored in the anterior pituitary gland² from their precursor protein proopiomelanocortin (POMC). However, recent studies suggest cells of the immune system are also capable of beta-endorphin synthesis because immune cells possess mRNA transcripts for POMC³ and T-lymphocytes, B-lymphocytes, monocytes and macrophages have been shown to contain endorphins during inflammation.^4–6

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 CRH 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 CRH production off - that is, feedback inhibition occurs.⁷

Mechanism of Action

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. 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.^4,8,9 In the PNS, 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.⁴

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.^8,9 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.⁸

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 CNS and 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.^11,12 In similar studies, Hargreaves et al. 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.^13,14

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.^15–17 And Zhang et al. found that mu-opioid receptors on beta-endorphin containing neurons of the hypothalamus of guinea pigs decreased in density after chronic-morphine treatment.¹⁸ Furthermore, Christie et al. 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.¹⁹

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 (OIH), 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.²⁰ While down regulation of both endorphins and mu receptors associated with chronic exogenous opioid use likely play a role in OIH, 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.²¹ 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.²² Addiction is described as a brain disease resulting in a loss of control over drug taking or in compulsive drug seeking, despite noxious consequences.²³ While the aforementioned mechanisms associated with OIH 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. As mentioned previously, 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.¹⁵ 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.²⁴ 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. concluded that endorphins are most likely excreted in response to postoperative pain.²⁵ Earlier studies have also found a negative correlation between intra-operative plasma beta-endorphin concentration and postoperative pain severity.^13,26

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,²⁷ suggesting either rofecoxib supports beta-endorphin synthesis, durability or both or acetaminophen inhibits it. Additionally, Parsa et al. demonstrated decreased postoperative pain severity and opioid requirements following preoperative administration of celecoxib plus gabapentin.²⁸ 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.

In review, beta-endorphins are proteins that are primarily synthesized by the pituitary gland in response to physiologic stressors such as pain. They 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.

Disclaimer

The authors have no financial interest in the medications reported in this article.