Analgesic effect of a mixed T-type channel inhibitor/CB(2) receptor agonist

BACKGROUND: Cannabinoid receptors and T-type calcium channels are potential targets for treating pain. Here we report on the design, synthesis and analgesic properties of a new mixed cannabinoid/T-type channel ligand, NMP-181. RESULTS: NMP-181 action on CB(1) and CB(2) receptors was characterized in radioligand binding and in vitro GTPγ[(35)S] functional assays, and block of transiently expressed human Cav3.2 T-type channels by NMP-181 was analyzed by patch clamp. The analgesic effects and in vivo mechanism of action of NMP-181 delivered spinally or systemically were analyzed in formalin and CFA mouse models of pain. NMP-181 inhibited peak Ca(V)3.2 currents with IC(50) values in the low micromolar range and acted as a CB(2) agonist. Inactivated state dependence further augmented the inhibitory action of NMP-181. NMP-181 produced a dose-dependent antinociceptive effect when administered either spinally or systemically in both phases of the formalin test. Both i.t. and i.p. treatment of mice with NMP-181 reversed the mechanical hyperalgesia induced by CFA injection. NMP-181 showed no antinocieptive effect in Ca(V)3.2 null mice. The antinociceptive effect of intrathecally delivered NMP-181 in the formalin test was reversed by i.t. treatment of mice with AM-630 (CB(2) antagonist). In contrast, the NMP-181-induced antinociception was not affected by treatment of mice with AM-281 (CB(1) antagonist). CONCLUSIONS: Our work shows that both T-type channels as well as CB(2) receptors play a role in the antinociceptive action of NMP-181, and also provides a novel avenue for suppressing chronic pain through novel mixed T-type/cannabinoid receptor ligands.