Endorphins

Endorphins are endogenous peptide compounds produced primarily in the brain that function as natural analgesics and mood enhancers. They are stored and released mainly by the pituitary gland and are also synthesised in smaller quantities in the adrenal medulla. These peptides reduce the perception of pain, alleviate muscle cramps, minimise stress responses, and generate sensations of wellbeing. Endorphins are commonly released during physical exercise, meditation, and orgasm, forming part of the body’s intrinsic mechanism for coping with discomfort and promoting emotional balance.

Historical Background

The discovery of opioid peptides emerged in the early 1970s during investigations into the brain’s response to pain and the pharmacology of opioids. In 1973, John Hughes and Hans Kosterlitz at the University of Aberdeen isolated the first enkephalins—Met-enkephalin and Leu-enkephalin—from pig brain tissue, leading to the identification of naturally occurring ligands for opioid receptors. Their discovery followed earlier identification of opioid receptors, which provided a theoretical basis for the existence of endogenous opioid substances.
Around the same period, Rabi Simantov and Solomon Snyder isolated further morphine-like peptides from animal brain tissue, and Eric J. Simon coined the term ‘endorphins’ to describe endogenous compounds demonstrating morphine-like effects. In 1976, Choh Hao Li and David Chung identified and sequenced endorphin peptides from camel pituitary glands, confirming their potent analgesic activity. Subsequent studies demonstrated that endorphin could exceed morphine in analgesic strength, with its effects reversible by naloxone, an opioid antagonist.
By the late 1970s, research distinguished between enkephalins, endorphins, and endogenously produced morphine-like compounds that are not peptides. Investigations also clarified that opioid peptides are classified according to the propeptide from which they originate: endorphins from proopiomelanocortin (POMC), enkephalins from proenkephalin A, and dynorphins from prodynorphin.

Etymology

The word ‘endorphin’ is derived from the combination of ‘endogenous’, meaning ‘from within’, and ‘morphine’, named after Morpheus, the Greek god of dreams. The term refers to naturally produced substances within the body that mimic the pharmacological actions of morphine.

Types of Endorphins

Endorphins constitute a subgroup of endogenous opioid peptides. The principal members of this class are α-endorphin, β-endorphin, and γ-endorphin, all derived from the precursor protein POMC. These peptides share a characteristic Met-enkephalin sequence at their N-terminus (Tyr-Gly-Gly-Phe-Met).
The structural differences arise from proteolytic cleavage:

• α-endorphin is the shortest of the three peptides.
• β-endorphin is the longest and the best-studied due to its strong affinity for opioid receptors and its pronounced analgesic activity.
• γ-endorphin has an intermediate sequence length.

α-endorphin and γ-endorphin, though structurally related to β-endorphin, do not demonstrate significant affinity for classical opioid receptors. Some studies have proposed that α-endorphin may exhibit stimulant-like effects, whereas γ-endorphin may act in a manner akin to neuroleptic compounds. The endorphins are primarily concentrated in the anterior and intermediate lobes of the pituitary gland.

Synthesis and Processing

Endorphin synthesis begins with the transcription and translation of the POMC gene in the pituitary gland. Within the trans-Golgi network, POMC associates with carboxypeptidase E, a membrane-bound sorting receptor that directs the precursor into secretory vesicles.
Post-translational processing occurs through a sequence of enzymatic cleavages:

• Prohormone convertase 1 (PC1) cleaves POMC to produce adrenocorticotropic hormone (ACTH) and β-lipotropin (β-LPH).
• β-LPH undergoes further enzymatic cleavage to generate β-endorphin, α-endorphin, and γ-endorphin.
• Prohormone convertase 2 (PC2) catalyses additional steps, particularly the conversion of β-LPH into β-endorphin and related peptides.

Endorphin synthesis is regulated by physiological factors. Norepinephrine, for example, can stimulate endorphin production in inflamed tissues, contributing to localised analgesic responses. Electroacupuncture has also been shown to enhance sympathetic activation, thereby promoting endorphin release.

Mechanism of Action

Endorphins operate within both the central nervous system (CNS) and the peripheral nervous system (PNS). Their release is typically triggered by painful stimuli or stress.
In the PNS, β-endorphin is the chief endorphin secreted from the pituitary gland into the bloodstream. It binds to opioid receptors on peripheral nerve endings, inhibiting the release of substance P, a neurotransmitter crucial for transmitting pain signals.
In the CNS, endorphins modulate neuronal activity by inhibiting the release of gamma-aminobutyric acid (GABA). Because GABA normally suppresses dopamine-producing neurons, its inhibition leads to increased dopamine release, reinforcing sensations of reward, pleasure, and learning. This dopaminergic modulation underpins many of the mood-enhancing effects associated with endorphin release.

Functions and Physiological Roles

Endorphins play a central role in the body’s natural pain-inhibition pathways. Their functions span emotional, physiological, and behavioural domains:

• Pain modulation: Endorphins diminish pain perception during injury or stress.
• Stress reduction: They contribute to stress buffering by reducing anxiety and promoting relaxation.
• Exercise response: Vigorous aerobic exercise stimulates endorphin release, traditionally thought to explain the ‘runner’s high’. However, recent studies suggest that endocannabinoids may play a more significant role, although endorphins still influence mood regulation associated with exercise.
• Emotional wellbeing: Endorphins aid in regulating anxiety disorders and depressive conditions through mood-elevating and anxiolytic effects.
• Meditation and laughter: Both activities have been shown to stimulate endorphin release and elevate pain thresholds.
• Exercise addiction: Chronic intense exercise may downregulate endorphin production at rest, prompting individuals to seek increasingly strenuous activity to achieve the same subjective sensation of wellbeing.