A patient on morphine for cancer pain develops tolerance. Which pharmacological process most contributes to opioid tolerance at the molecular level?
- A Downregulation of mu-opioid receptor gene transcription, reducing receptor synthesis
- B Upregulation of adenylyl cyclase isozymes in neurons, compensating for opioid-mediated cAMP suppression ('cAMP overshoot' is purely a withdrawal phenomenon)
- C Receptor desensitisation via GRK (G-protein receptor kinase)-mediated phosphorylation of the mu-opioid receptor and beta-arrestin recruitment, causing uncoupling from G-protein signalling and internalisation ✓
- D Increased NAD+-dependent NMDA receptor activation that competitively opposes mu-receptor analgesia
Correct answer: C. Receptor desensitisation via GRK (G-protein receptor kinase)-mediated phosphorylation of the mu-opioid receptor and beta-arrestin recruitment, causing uncoupling from G-protein signalling and internalisation
Explanation
Opioid tolerance develops primarily through receptor-level desensitisation. Chronic mu-opioid receptor activation recruits GRK2/3, which phosphorylates the receptor's intracellular C-terminal tail. Beta-arrestin then binds and uncouples the receptor from its Gi/o protein, terminating G-protein signalling. Prolonged beta-arrestin binding also triggers receptor internalisation (endocytosis), reducing surface receptor density. Upregulation of adenylyl cyclase (cAMP superactivation) underlies the withdrawal hyperalgesia, not tolerance per se.
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.