Long-term opioid therapy leads to tolerance. The cellular mechanism most responsible for analgesic tolerance is:

• A Decreased synthesis of endogenous opioid peptides
• B Downregulation of NMDA glutamate receptors reducing central sensitisation
• C Upregulation of adenylyl cyclase (AC superactivation), GPCR uncoupling from G-proteins, and receptor internalisation reducing functional μ-receptor density ✓
• D Increased hepatic CYP3A4 expression accelerating opioid metabolism

Explanation

Opioid tolerance involves multiple molecular adaptations: (1) GPCR kinase (GRK)-mediated receptor phosphorylation and β-arrestin binding uncouples μ-opioid receptors from Gi proteins; (2) receptor internalisation removes surface receptors; (3) prolonged Gi inhibition of adenylyl cyclase leads to compensatory AC superactivation, requiring increasing opioid to suppress cAMP. NMDA receptor upregulation (not downregulation) occurs with chronic opioid use and contributes to hyperalgesia; NMDA antagonists (ketamine, methadone's NMDA antagonism) can partially reverse tolerance.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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