Spinally delivered N-, P/Q- and L-type Ca2+-channel blockers potentiate morphine analgesia in mice.
We studied the antinociceptive effects induced at the spinal level by N-, P/Q- and L-type voltage-dependent Ca2+-channel (VDCC) blockers given alone or in combination with morphine, the test responses being the algesic ones induced by acute thermal and mechanical stimuli. When given alone, intrathecal omega-agatoxin IVA (P/Q-type blocker) produced a potent dose-dependent inhibition in the tail-flick and tail-pressure over the dose range 0.33-33 pmol/mouse. Omega-conotoxin GVIA (N-type blocker) also produced dose-dependent inhibitions, but its antinociception against thermal stimuli was weaker than against mechanical stimuli. Calciseptine (L-type blocker) slightly reduced both nociceptive responses, but only at 33 pmol. At their subthreshold doses, intrathecal omega-agatoxin IVA, omega-conotoxin GVIA and calciseptine each significantly enhanced morphine analgesia in the tail-flick and tail-pressure tests, the rank order of potencies being N-> or =P/Q->L-type. These results indicate that combining a low-dose VDCC blocker, especially the N- or P/Q-type, with morphine may be a very useful way of minimizing the dose of morphine and may reduce side effects.
D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000187:drug effects*; D020864:Calcium Channels, N-Type / Q000187:drug effects*; D020865:Calcium Channels, P-Type / Q000187:drug effects*; D020907:Calcium Channels, Q-Type / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006358:Hot Temperature; D007278:Injections, Spinal; D008297:Male; D051379:Mice; D009020:Morphine / Q000494:pharmacology*; D010147:Pain Measurement / Q000187:drug effects; D010812:Physical Stimulation; D004856:Postural Balance / Q000187:drug effects; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects
D000701:Analgesics, Opioid; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D020864:Calcium Channels, N-Type; D020865:Calcium Channels, P-Type; D020907:Calcium Channels, Q-Type; D009020:Morphine