Omega-agatoxin IVA blocks spinal morphine/clonidine antinociceptive synergism.
Involvement of P-type voltage-dependent Ca2+ channels in spinal morphine- or clonidine-induced antinociception and in the synergistic interaction between morphine and clonidine was examined in the present studies. Coadministration of the selective P-type antagonist, omega-agatoxin IVA (25 ng) intrathecally (i.t.) to mice along with morphine or clonidine enhanced the tail flick antinociception of each agonist 5-6-fold. The greater-than-additive (synergistic) interaction that occurred when morphine and clonidine were coadministered i.t. decreased to an additive interaction in the presence of omega-agatoxin IVA. In mice pretreated with pertussis toxin (10 ng) to inactivate G proteins, omega-agatoxin IVA did not alter the morphine/clonidine synergism. Surprisingly, omega-agatoxin IVA reversed the additive morphine/clonidine interaction that occurs in morphine-tolerant mice back to synergism. These results suggest that functional P-type Ca2+ channels play an essential role in the antinociceptive synergism between spinal morphine and clonidine.
Roerig
S C
SC
Department of Pharmacology, Louisiana State University Medical Center, Shreveport 71130, USA.
Howse
K M
KM
D000701:Analgesics, Opioid / Q000037:antagonists & inhibitors*; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D003000:Clonidine / Q000037:antagonists & inhibitors*; D004357:Drug Synergism; D004361:Drug Tolerance; D016014:Linear Models; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009020:Morphine / Q000037:antagonists & inhibitors*; D009021:Morphine Dependence / Q000517:prevention & control; D037342:Pertussis Toxin; D013111:Spider Venoms / Q000494:pharmacology*; D013116:Spinal Cord / Q000187:drug effects*; D019966:Substance-Related Disorders / Q000517:prevention & control; D010566:Virulence Factors, Bordetella / Q000494:pharmacology; D020867:omega-Agatoxin IVA
D000701:Analgesics, Opioid; D002121:Calcium Channel Blockers; D013111:Spider Venoms; D010566:Virulence Factors, Bordetella; D020867:omega-Agatoxin IVA; D009020:Morphine; D037342:Pertussis Toxin; D003000:Clonidine