GPCRs: Opioid receptors

The 4 human opioid receptors are inhibitory G protein-coupled receptors that are part of a neuromodulatory system that regulates reward, aversion and mood, and modulates pain sensation (nociception).  The endogenous opioid receptor agonists are the peptide ligands β-endorphin, enkephalins, dynorphins and nociceptin/orphanin FQ. In general β-endorphin and the enkephalins are high affinity agonists for their receptors and the dynorphins have lower affinities.

To varying degrees, depending on ligand selectivity, this family of receptors are the targets of semisynthetic and synthetic opioids that are used as drugs (both therapeutically and illicitly).

The analgesic effect of clinically used opioids is principally mediated by the μ opioid receptor. Unfortunately, the μ opioid receptor is also the receptor that is responsible for the adverse actions of morphine (and other μ opioid receptor agonists). μ opioid receptor agonists induce tolerance, respiratory depression (the main cause of overdose) and drug dependence (contributing to addiction). Expression of μ opioid receptors in the gastrointestinal tract is responsible for opioid-induced constipation. 

The ‘opioid epidemic’ has driven the rapid evolution of synthetic opioid derivatives (referred to as novel synthetic opioids or NSOs), such as non-pharmaceutical fentanyls and the 2-benzylbenzimidazole ('nitazene') class of non-fentanyl type agonists. Many of the novel derivatives are significantly more potent μ opioid receptor agonists than morphine and fentanyl, and subsequently they are highly addictive and are associated with a severe risk of fatal overdose.

With regard to the other opioid receptors, the δ opioid receptor has anxiolytic and antidepressant functions, and may modulate chronic pain nociception. The κ opioid receptor activation produces aversive and psychotomimetic effects (causing delusions/delirium), and mediates an antipruritic effect. The nociceptin receptor is involved in the regulation of instinctive and emotional behaviours. Despite high sequence identity with μ, δ and k opioid receptors, the nociceptin receptor has negligible affinity for opioid peptides or morphine-like compounds.