Pharmacology of Endorphins and Enkephalins

Pharmacology of Endorphins and Enkephalins

1. Definition, scope and historical context

• Endogenous opioid peptides (EOPs) are naturally occurring peptide neurotransmitters/neuromodulators that bind with high affinity to opioid receptors and whose actions are blocked by the opioid antagonist naloxone; they constitute an endogenous opioid system that physiologically modulates pain perception, mood, hedonic and motor behaviour, emesis, pituitary-hormone release and gastrointestinal motility (KDT 8e Ch.34, p.513).
• The term opiate is reserved for morphine, codeine and structurally related natural and semi-synthetic alkaloids present in opium (the dried resin of Papaver somniferum); opioid is the broader pharmacological term covering ANY agent — exogenous or endogenous — that binds the orthosteric site of an opioid receptor, and therefore includes the enkephalins, endorphins, dynorphins, endomorphins, and nociceptin (G&G 14e Ch.23, pp.443–4).
• Three classical families of endogenous opioid peptides act on the classical opioid receptors:
  • β-Endorphin (and related endorphins) — principally μ > δ preferring
  • Met-enkephalin and Leu-enkephalin — δ ≥ μ preferring, no κ activity
  • Dynorphins (A, B, α/β-neoendorphin) — κ > μ = δ
  • A fourth family of endomorphins (endomorphin-1 and -2) binds the μ receptor with high affinity and selectivity, but their precursor protein has never been identified, so their truly endogenous status is debated (G&G 14e Ch.23, pp.444–7; KDT 8e Ch.34, p.513).
• A separate nociceptin/orphanin FQ (N/OFQ) system acts on the NOP (ORL-1) receptor; nociceptin and the NOP receptor are structurally related to the classical opioid family but their pharmacology is functionally distinct — enkephalins, endorphins and dynorphins do NOT bind NOPr, and nociceptin does NOT bind the classical receptors, and NOPr binding is NOT reversed by naloxone (G&G 14e Ch.23, pp.443–7; Katzung 16e Ch.31, p.583).
• Discovery timeline (postgraduate landmark):
  • Early 1970s — Pert and Snyder, and others, identified stereo-specific opioid binding sites in mammalian brain using radiolabelled naloxone, predicting the existence of endogenous ligands (R&D 10e Ch.43, p.30).
  • 1975 — Hughes and Kosterlitz isolated the first endogenous opioid peptides from pig brain — Met-enkephalin and Leu-enkephalin (R&D 10e Ch.43, pp.30–31).
  • Over the next decade, β-endorphin, dynorphins, endomorphins and finally nociceptin/orphanin FQ (1995) were characterised, expanding the system to >20 endogenous opioid peptides acting on four receptors (G&G 14e Ch.23, p.445).
• Why MD-level study matters: endogenous opioids underpin descending pain modulation, placebo analgesia, stress-induced analgesia, acupuncture analgesia, exercise-related mood elevation, reward-circuit regulation, neuroendocrine control, GI motility, and opioid use disorder, and they explain why exogenous opioid drugs work (G&G 14e Ch.23, pp.444–9; KDT 8e Ch.34, p.513; R&D 10e Ch.43, pp.32–35).