Biochemistry, Endorphin

Fundamentals

The endogenous opioid system comprises 3 primary families of opioid neuropeptides: β-endorphins, enkephalins, and dynorphins. Each family serves as a natural ligand for the classical μ, δ, and κ opioid receptors. These neuropeptides are not synthesized in their active forms but arise through proteolytic cleavage of larger polypeptide precursors. β-Endorphins derive from proopiomelanocortin (POMC), enkephalins from proenkephalin (PENK), and dynorphins from prodynorphin (PDYN). Differential binding affinities for the 3 major opioid receptors underlie the distinct physiological effects of these endogenous ligands.[4]

Issues of Concern

Opioid agonists are highly effective for treating acute and chronic pain but present several significant clinical and societal challenges. The group's mechanism of action, binding to and activating MORs, produces analgesia as well as a range of adverse effects, including respiratory depression, sedation, constipation, and nausea.

A major concern is the development of tolerance, in which increasing doses are required to achieve the same analgesic effect, and physical dependence, which can lead to withdrawal symptoms upon cessation. Sudden reduction or discontinuation of opioid administration triggers withdrawal, reflecting the body’s struggle to reestablish equilibrium in the absence of the substance.

Prolonged use can also cause OIH, a paradoxical increase in pain sensitivity. Additionally, the high potential for misuse, addiction, and diversion, especially with potent synthetic opioids such as fentanyl, has contributed to a global public health crisis marked by escalating overdose deaths.[5]

Cellular Level

The precursors of endogenous opioid ligands are encoded by distinct genes, POMC, PENK, and PDYN, and are differentially expressed across regions of the central and peripheral nervous systems. Enzymatic processing of these precursors generates a variety of bioactive opioid peptides, each with unique affinities for μ, δ, and κ receptors and distinct physiological roles, including modulation of pain, stress responses, reward, and mood.

Despite their diversity in sequence and function, classical opioid peptides share a highly conserved N-terminal tetrapeptide motif, Tyr-Gly-Gly-Phe, which is critical for receptor recognition and activation. This motif enables engagement of the orthosteric binding site of opioid receptors, initiating conformational changes that underlie receptor signaling.

In addition to the 3 classical opioid systems, a 4th gene, PNOC, encodes pronociceptin, the precursor of the neuropeptide nociceptin. This neuropeptide is also known as nociceptin/orphanin FQ, a name derived from its N-terminal phenylalanine and glutamine. Unlike classical opioid peptides, nociceptin lacks the conserved N-terminal tetrapeptide, a key determinant for binding to μ, δ, or κ receptors. Although PNOC shares some sequence homology with PDYN, mature nociceptin exhibits negligible affinity for classical opioid receptors.

Nociceptin acts through a distinct GPCR, the NOP. The nociceptin-NOP system constitutes a functionally separate branch of the endogenous opioid system, with unique pharmacological and physiological properties. This branch plays a crucial role in modulating or counterbalancing classical opioid signaling, particularly in pain modulation, reward processing, and stress responses.

Molecular Level

Endorphins originate from the precursor polypeptide POMC, a multifunctional prohormone primarily synthesized in the anterior pituitary gland. Recent research has expanded the understanding of POMC expression, revealing its synthesis in cells of the immune system and suggesting a potential role for immune-derived endorphins in modulating pain and inflammation. POMC consists of a 241-amino acid sequence, which undergoes posttranslational processing by specific prohormone convertases to yield several biologically active peptides. A key intermediate in this process is β-lipotropin, a 93-amino acid polypeptide further cleaved enzymatically to produce β-melanocyte-stimulating hormone and a family of endorphins.

Endorphins are classified into 3 structurally related peptides: α-, β-, and γ-endorphins. Among these molecules, β-endorphin is the longest and most physiologically significant, consisting of a 31-amino acid sequence, as follows:

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-Glu.

This sequence corresponds to amino acids 104 to 134 of β-lipotropin, highlighting the specific region from which it is derived.

γ-endorphin, the second longest, comprises the first 17 amino acids of β-endorphin, while α-endorphin consists of the initial 16 amino acids. The shorter endorphins, α and γ, are effectively nested within the β-endorphin sequence, sharing identical N-terminal segments. This conserved region is particularly important, as it includes the Tyr-Gly-Gly-Phe motif critical for binding to opioid receptors.

These structural features enable endorphins to function as endogenous agonists at the μ, δ, and κ opioid receptors, which are also targets for exogenous opiate drugs such as morphine. Through these receptor interactions, endorphins mediate a range of physiological responses, including analgesia, stress modulation, and reward signaling, aligning their function with both innate and pharmacologically induced opioid effects.[6][7][8]

Function

Endorphins play a critical role in the body’s natural pain regulation and reward systems. These molecules are released in response to pain or stress, producing analgesic effects that, in some cases, surpass the efficacy of morphine. Among the different types, β-endorphin is the most extensively studied and is a major contributor to the well-documented phenomenon of exercise-induced euphoria, commonly referred to as the “runner’s high.” In addition to analgesia, endorphins are associated with states of pleasure and emotional well-being, including those elicited by laughter, romantic love, sexual activity, and the consumption of palatable food.

Endorphins exhibit functional duality depending on their site of action. These peptides act as neurotransmitters or neuromodulators within the central nervous system and as hormones when released from the pituitary gland into systemic circulation. Among the main classes—α-, β-, and γ-endorphins, enkephalins, and dynorphins—β-endorphins dominate in systemic analgesic potency and are the most functionally characterized. Ongoing research continues to investigate the distinct roles of each endorphin subtype, aiming to deepen understanding of their physiological effects and therapeutic potential in conditions such as chronic pain, mood disorders, and addiction.[9][10]

Opioid Agonists

Morphine, first isolated from opium in 1806 by Friedrich Sertürner, was named after Morpheus, the Greek god of sleep, in reference to its potent sedative and hypnotic properties. This substance remains one of the most widely used opioids for managing acute and severe chronic pain. Like other opioids, morphine displays affinity for μ, δ, and κ receptors. Mechanistically, morphine reduces nociceptive transmission by inhibiting signaling between 1st- and 2nd-order neurons in the dorsal horn of the spinal cord. This opiate also enhances descending inhibitory pathways within the central nervous system and is thought to attenuate nociceptive input at the level of peripheral afferent neurons. Prolonged administration often leads to tolerance, OIH, and physical dependence, which can limit long-term utility.

Morphine serves as the prototypical opiate and provides the chemical backbone for a wide class of opioid compounds. Structural modifications of the morphine molecule yield semisynthetic opioids, such as oxycodone and heroin. Oxycodone acts as a selective MOR agonist.

Fentanyl and its analogues are synthetic opioids that act as full agonists at the MOR, exhibiting significantly higher potency than morphine. Fentanyl is estimated to be 70 to 100 times more potent than morphine, producing profound analgesic effects at much lower doses. This high potency results from its strong affinity for MORs and rapid penetration of the blood-brain barrier, producing a fast onset of action.[11][12]

Mechanism

Opioid Receptors and Signaling Transduction

The human genome encodes 4 main opioid receptors, all members of the GPCR superfamily. These receptors include the μ, δ, and κ receptors, as well as the NOP, previously known as opioid receptor-like 1 (ORL1). Each receptor contains 7 transmembrane domains and couples primarily to the inhibitory G proteins, Gαi and Gαo. Binding of an endogenous or exogenous opioid agonist to the extracellular N-terminal domain induces a conformational change that activates the associated G protein. The Gαi and Gαo subunits then exchange guanosine diphosphate (GDP) for guanosine triphosphate (GTP), dissociating from the Gβγ dimer and triggering downstream signaling events that collectively reduce neuronal excitability and neurotransmitter release.

A key consequence of opioid receptor activation is inhibition of adenylate cyclase, which decreases cyclic adenosine monophosphate (cAMP) production. The receptors modulate ion channels simultaneously to suppress synaptic transmission further. The Gβγ subunit inhibits voltage-gated calcium channels, reducing calcium influx and impairing vesicular neurotransmitter release. The Gα subunit can directly activate G protein-gated inwardly rectifying potassium (GIRK/Kir3) channels, promoting cellular hyperpolarization and suppressing tonic neural firing. Beyond these canonical pathways, opioid receptors also engage phospholipase C (PLC) and activate the mitogen-activated protein kinase (MAPK) cascade, indicating broader roles in gene expression, cellular plasticity, and long-term neuronal adaptation.[13]

Clinical Significance

From a clinical perspective, the physiological roles and therapeutic implications of endorphins remain under active investigation. One important pharmacological interaction involves naloxone, an opioid antagonist commonly used to reverse opioid overdose. Naloxone competitively binds to opioid receptors, displacing both exogenous opioids and endogenous ligands such as endorphins. This antagonism not only blocks opioid-induced respiratory depression but can also inhibit normal endorphin signaling. Interestingly, naloxone has demonstrated therapeutic potential in conditions such as depersonalization disorder, where administration of the drug has led to symptomatic improvement. This observation suggests a possible role for dysregulated endorphin activity in the pathophysiology of dissociative disorders.

Another clinically significant area of study concerns the relationship between chronic opioid dependence and hypothalamo-pituitary-gonadal axis dysfunction. Evidence indicates that β-endorphins influence luteinizing hormone secretion from the anterior pituitary by modulating gonadotropin-releasing hormone. Chronic opioid use can disrupt this regulatory pathway, leading to reduced gonadal hormone production and subsequent reproductive dysfunction, an increasingly recognized complication of long-term opioid therapy.

Modulation of β-endorphin levels by different classes of analgesics has raised important questions regarding their role in pain perception and treatment efficacy. Studies in postsurgical patients comparing opioid and nonopioid analgesics have shown that β-endorphin levels increase significantly following opioid administration, reflecting both physiological pain responses and drug-induced enhancement. Interestingly, acetaminophen appears to suppress β-endorphin levels, whereas the COX-2 inhibitor rofecoxib does not, despite its effective analgesic action. These findings suggest that certain nonopioid analgesics can achieve pain relief without interfering with endogenous opioid pathways, opening avenues for developing safer alternatives that avoid opioid-associated risks such as tolerance, dependence, and addiction.[14][15]