Influence of voltage-sensitive Ca++ channel drugs on bupivacaine infiltration anesthesia in mice

Background: Local anesthesia has been traditionally associated with blockad e of voltage-sensitive sodium (Na+) channels. Yet in vitro evidence indicat es that local anesthetic mechanisms are more complex than previously unders tood. For example, local anesthetics bind and allosterically modify 1,4-dih ydropyridine-sensitive Ca++ channels and can reduce Ca++ influx in tissues. The current study examines the influence of voltage-sensitive Ca++ channel s in bupivacaine infiltration anesthesia. Methods: Baseline tail-flick latencies to radiant heat nociception were obt ained before subcutaneous infiltration of bupivacaine and Ca++-modulating d rugs in the tails of mice. No musculature is contained in the tail that cou ld result in motor block. The magnitude of infiltration anesthesia over tim e, as well as the potency of bupivacaine alone or in the presence of Ca++-m odulating drug, was assessed by obtaining test latencies. Results: The 1,4-dihydropyridine L-type Ca++ channel agonist S(-)-BayK-8644 reduced the duration of action and potency of bupivacaine anesthesia. In o pposite fashion, nifedipine and nicardipine increased the effects of bupiva caine. Neither nifedipine nor nicardipine alone elicited anesthesia. Altern atively, the phenylalkylamine L-type blocker verapamil elicited concentrati on-dependent anesthesia. Other Ca++ channel subtype blockers were investiga ted as well. The N-, T-, P-, and Q-type channel blockers, omega -conotoxin GVIA, flunarizine, omega -agatoxin IVA, and omega -conotoxin MVIIC, respect ively, were unable to modify bupivacaine anesthesia. Conclusions. These results indicate that heat nociception stimulates Ca++ i nflux through L-type channels on nociceptors in skin. Although other voltag e-sensitive Ca++ channels may be located on skin nociceptors, only the L-ty pe channel drugs affected bupivacaine in the radiant heat test.