Calcium modulation of morphine analgesia: role of calcium channels and intracellular pool calcium.
Calcium (Ca++) administered into the i.c.v. space of mice has been reported to block opioid-induced antinociception dose dependently. These studies were conducted to test the hypothesis that Ca++ i.c.v. blocks the antinociceptive effects of morphine i.c.v. as a consequence of transmembrane Ca++ influx and Ca++ release from intracellular pools. Mice were injected with voltage-sensitive Ca++ channel antagonists at a dose that did not affect morphine antinociception to determine whether this pretreatment would prevent the inhibitory effects of Ca++. Nimodipine (12 nmol i.c.v.) was ineffective in preventing the inhibitory effects of Ca++ (100 nmol i.c.v.), whereas omega-conotoxin GVIA (3.3 pmol i.c.v.) completely prevented the inhibition by Ca++ of morphine antinociception. Other experiments were conducted to determine whether blocking Ca++ release from Ca++/caffeine-sensitive microsomal pools with ryanodine would prevent the inhibitory effects of Ca++. Ryanodine (2 nmol i.c.v.) significantly attenuated the inhibition by Ca++ of morphine antinociception. Another hypothesis to be tested was that stimulation of Ca++ release from intracellular pools would, like Ca++, block morphine antinociception. Thapsigargin (0.002-30 nmol i.c.v.), which increases cytosolic Ca++ by depleting Ca++ from inositol 1,4,5-trisphosphate-sensitive microsomal pools, dose-dependently blocked the antinociceptive effects of morphine. The results of this study indicate that Ca++ blocked morphine antinociception by stimulating Ca++ influx through omega-conotoxin GVIA-sensitive channels and by stimulating Ca++ release from Ca++/caffeine-sensitive microsomal pools.
Smith
F L
FL
Department of Pharmacology and Toxicology, Medical College of Virginia/Virginia Commonwealth University, Richmond.
Stevens
D L
DL
D000818:Animals; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000502:physiology*; D015220:Calcium Channels / Q000502:physiology*; D002451:Cell Compartmentation / Q000187:drug effects; D008297:Male; D008564:Membrane Potentials; D051379:Mice; D008815:Mice, Inbred Strains; D008861:Microsomes / Q000378:metabolism; D009020:Morphine / Q000494:pharmacology*; D009553:Nimodipine / Q000494:pharmacology; D010146:Pain / Q000503:physiopathology*; D010455:Peptides / Q000494:pharmacology; D012433:Ryanodine / Q000494:pharmacology; D013729:Terpenes / Q000494:pharmacology; D019284:Thapsigargin; D020866:omega-Conotoxin GVIA
D015220:Calcium Channels; D010455:Peptides; D013729:Terpenes; D012433:Ryanodine; D002110:Caffeine; D009553:Nimodipine; D019284:Thapsigargin; D009020:Morphine; D020866:omega-Conotoxin GVIA; D002118:Calcium