Spinal morphine/clonidine antinociceptive synergism: involvement of G proteins and N-type voltage-dependent calcium channels.
When morphine and clonidine are coadministered into the spinal cord (intrathecally) the resulting antinociception is greater than would be expected if the drug responses were additive; thus, a synergistic interaction. The mechanism for this synergistic interaction was investigated using agents which alter calcium channel function and G protein function. Drugs were administered intrathecally to mice and antinociception was measured using the tail flick test. The L-type calcium channel antagonists nifedipine (15 micrograms) and verapamil (15 micrograms) and the N-type antagonist omega-conotoxin GVIA (3 and 30 ng) decreased ED50 values for both morphine and clonidine three-to five-fold. The L-type calcium channel activator Bay K 8644 had a biphasic effect; 1.7 ng increased, although 170 ng decreased, morphine and clonidine ED50 values. None of the calcium channel modifiers affected the morphine/clonidine synergism. In mice pretreated with pertussis toxin (PTX, one, 10-ng dose 21 days previously), the morphine ED50 value increased two-fold, although the clonidine ED50 value was not changed. PTX pretreatment did not alter the morphine/clonidine synergism. Also, in PTX-pretreated mice, nifedipine and 1.7 ng Bay K 8644 did not alter the morphine/clonidine synergism. However, in PTX-pretreated animals omega-conotoxin GVIA (3 ng) changed the morphine/clonidine synergism to an additive interaction. Thus, both N-type calcium channels and PTX-sensitive G proteins are likely involved in spinal morphine/clonidine synergism.
Wei
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Department of Pharmacology, Louisiana State University Medical Center, Shreveport, USA.
Karim
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Roerig
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D000701:Analgesics, Opioid / Q000008:administration & dosage*; D000818:Animals; D002118:Calcium / Q000502:physiology*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000502:physiology*; D003000:Clonidine / Q000008:administration & dosage*; D004357:Drug Synergism; D019204:GTP-Binding Proteins / Q000502:physiology*; D015640:Ion Channel Gating; D008297:Male; D008564:Membrane Potentials; D051379:Mice; D009020:Morphine / Q000008:administration & dosage*; D010146:Pain / Q000517:prevention & control; D037342:Pertussis Toxin; D018341:Receptors, Adrenergic, alpha-2 / Q000502:physiology*; D015398:Signal Transduction; D013116:Spinal Cord / Q000187:drug effects; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D000701:Analgesics, Opioid; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D018341:Receptors, Adrenergic, alpha-2; D010566:Virulence Factors, Bordetella; D009020:Morphine; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins; D003000:Clonidine; D002118:Calcium