Involvement of Intracellular Calcium in Morphine Tolerance in Mice

• Published in: Pharmacology, biochemistry and behavior biochemistry and behavior, 1999-02, Vol.62 (2), p.381-388
• Main Authors: Smith, Forrest L., Dombrowski, Daniel S., Dewey, William L.
• Format: Article
• Language: English
• Subjects: Analgesia; Analgesics; Analgesics, Opioid - pharmacology; Animals; Biological and medical sciences; Biological Transport; Caffeine - pharmacology; Calcium - metabolism; Calcium Channels - metabolism; Central Nervous System Stimulants - pharmacology; Dose-Response Relationship, Drug; Drug Interactions; Drug Tolerance - physiology; Intracellular calcium; Male; Medical sciences; Mice; Microsomes - drug effects; Microsomes - metabolism; Morphine - pharmacology; Morphine tolerance; Neuropharmacology; Pharmacology. Drug treatments
• ISSN: 0091-3057; 1873-5177
• DOI: 10.1016/S0091-3057(98)00168-3

Opioid analgesic tolerance is associated with a disruption in Ca ++ homeostasis. Drugs reducing Ca ++ influx can prevent and reverse tolerance. The hypothesis was tested that both Ca ++ influx and mobilization from intracellular pools maintains the expression of morphine tolerance. Ca ++ modulating drugs were injected ICV at doses not affecting morphine’s potency in placebo pellet-implanted mice, in order to determine whether tolerance would be reversed in morphine pellet-implanted mice. The Ca ++ chelator EGTA significantly reversed tolerance. The Ca ++ channel antagonists nifedipine and omega-conotoxin GVIA also reversed tolerance. The role of intracellular Ca ++ was investigated using the membrane permeable intracellular Ca ++ chelator EGTA-AM. EGTA-AM reversed tolerance at lower morphine doses, but not at higher morphine doses. Thus, mobilization of intracellular Ca ++ contributes to the expression of tolerance. Finally, 1,4-dihydropyridine–sensitive Ca ++ channels are known to stimulate Ca ++-induced Ca ++ release (CICR) from Ca ++/caffeine-sensitive microsomal pools possessing ryanodine receptors. We examined whether blocking Ca ++ mobilization from these pools with ryanodine would reverse morphine tolerance. Ryanodine’s effects were similar to EGTA-AM. Tolerance was reversed at lower morphine doses, but not at higher doses. Thus, morphine tolerance appears to be associated with increases in Ca ++ influx and mobilization from Ca ++/caffeine-sensitive pools.