A patient on long-term morphine therapy develops tolerance to analgesia but not to constipation. The explanation for this selectivity of tolerance is:

• A The GI myenteric plexus lacks mu-opioid receptors that can undergo desensitisation
• B Intestinal morphine metabolism generates an active metabolite specifically sustaining GI effects
• C Constipation is mediated by peripheral mu-opioid receptors on enteric neurons that undergo less desensitisation/internalisation than CNS receptors, and is not overcome by endogenous opioid competition ✓
• D Constipation is mediated by kappa receptors, which do not develop tolerance

Explanation

Tolerance to opioid effects develops differentially: CNS effects (analgesia, euphoria, respiratory depression) are subject to receptor desensitisation (uncoupling of receptor from Gi protein), downregulation, and upregulation of adenylyl cyclase ('cAMP overshoot'). In contrast, peripheral mu-receptors on myenteric plexus neurons undergo less desensitisation, and GI motility inhibition is not countered by endogenous opioid peptides (which have low levels in the gut). The result is persistent constipation even as analgesic tolerance develops—a well-documented clinical phenomenon addressed by peripherally restricted mu-antagonists like methylnaltrexone.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.