Mu opioid receptor (MOR)

The Mu opioid receptor (MOR) is a G protein-coupled receptor that serves as the primary mediator for the effects of both endogenous opioid peptides and clinical analgesic drugs like morphine and fentanyl (UniProt P35372). It is centrally involved in the regulation of pain, reward, and autonomic functions such as respiration. Recent structural and pharmacological evidence has identified a unique allosteric binding site within the MOR's extracellular vestibule that specifically recognizes the endogenous catecholamines epinephrine and norepinephrine (He et al., 2024, Nature). This allosteric site is distinct from the orthosteric pocket where traditional opioids bind, and its occupation by epinephrine enhances the potency and efficacy of orthosteric agonists. This mechanism is thought to underlie stress-induced analgesia, where the body's 'fight-or-flight' response naturally boosts the pain-relieving effects of the opioid system. From a drug development perspective, targeting this epinephrine allosteric site offers a promising strategy to create next-generation analgesics that may provide effective pain relief with a reduced risk of the lethal side effects typically associated with orthosteric MOR activation, such as respiratory arrest and addiction (PubMed 38123681).

Other names

OPRM1Mu-type opioid receptorMOPMOR-1Epinephrine allosteric siteOpioid receptor mu 1

Orthosteric agonists bind to the main pocket to activate Gi/o proteins, inhibiting adenylyl cyclase and modulating ion channels; epinephrine acts as a positive allosteric modulator (PAM) at a distinct extracellular site to enhance agonist affinity and signaling (He et al., 2024, Nature).