Anaes · Anaesthetic adjuncts

Opioid receptors, biased agonism, tolerance and opioid-induced hyperalgesia

Also known as Mu, kappa and delta opioid receptors · G-protein-biased opioid agonism and oliceridine · Opioid-induced hyperalgesia (OIH)

Opioid receptors are a family of G-protein-coupled receptors — the mu (MOR), kappa (KOR) and delta (DOR) — that mediate the analgesic and adverse effects of all clinically used opioids, together with a naloxone-insensitive fourth member, the NOP (nociceptin or orphanin FQ) receptor. All three classical receptors couple to inhibitory Gi/Go proteins, inhibiting adenylate cyclase, closing voltage-gated calcium channels and opening potassium channels, which hyperpolarises the nociceptive neurone and reduces release of substance P and glutamate. The mu receptor is the principal target of most clinical opioids (morphine, fentanyl) and mediates supraspinal and spinal analgesia, euphoria, respiratory depression, miosis and constipation; the kappa receptor mediates spinal analgesia with dysphoria and psychotomimetic effects but less respiratory depression; the delta receptor contributes to analgesia and is convulsant at high doses. Biased agonism — the concept that different ligands stabilise different receptor conformations to preferentially drive G-protein (analgesic) over beta-arrestin (adverse-effect) signalling — underpins drugs such as oliceridine. Repeated opioid exposure produces tolerance, a pharmacodynamic loss of effect through receptor desensitisation, downregulation and internalisation, and, distinct from tolerance, opioid-induced hyperalgesia (OIH), a paradoxical increase in pain sensitivity driven by central sensitisation, NMDA receptor activation, descending facilitation, glial activation and dynorphin. OIH is managed by opioid reduction or rotation and by NMDA antagonists (ketamine, methadone), alpha-2 agonists and multimodal non-opioid analgesia.