Voltage-sensitive calcium channels in spinal nociceptive processing: blockade of N- and P-type channels inhibits formalin-induced nociception.

The role of spinal voltage-sensitive calcium channels (VSCC) in a behavioral model of prolonged nociception was examined in rats. Blockade of VSCC by the trivalent cations neodymium (NdCl3) and lanthanum (LaCl3) resulted in a dose-dependent suppression of both phases of the response to formalin. omega-Conopeptides, which selectively block N-type VSCC, also produced a dose-dependent inhibition of both the initial behavior [phase 1; ED50 (nmol): SNX-111 (0.003) > SNX-185 (0.010) > SNX-239 (0.16) >> SNX-159 (> 0.26); SNX-199 (> 0.30)] and the facilitated response [phase 2; ED50 (nmol): SNX-111 (0.003) > SNX-185 (0.009) > SNX-239 (0.020) > SNX-159 (0.120) = SNX-199 (0.230)]. In contrast, SNX-231 (0.24 nmol), which is selective for a non-L/non-N site and also the L-type VSCC blockers nifedipine (24 nmol), nimodipine (29 nmol), verapamil (200 nmol), and diltiazem (220 nmol), had minimal effects on either phase of the formalin test at the highest dose examined. The P-type channel blocker omega-agatoxin IVA produced a 40% inhibition of phase 1 at the highest dose and phase 2 was suppressed in a dose-dependent fashion (ED50, 0.001 nmol). The response latency to a high-threshold thermal stimulus (the 52.5 degrees C hot plate) was moderately (20%) increased by NdCl3 (0.30 nmol) and SNX-111 (0.008 nmol), but not verapamil (200 nmol) and omega-agatoxin IVA (0.006 nmol). High doses of the N-type VSCC produced characteristic shaking behavior, serpentine-like tail movements, and impaired coordination. However, at antinociceptive doses there was no significant motor effect, though three of the N-type antagonists produced some tail movements. These studies demonstrate that VSCC of the N- and P-type, but not L-type, are involved in facilitated nociceptive processing at the spinal level.