Analgesia by intrathecal delta-9-tetrahydrocannabinol is dependent on Cav3.2 calcium channels

Delta-9-tetrahydrocannabinol (Δ⁹-THC) is known to produce systemic analgesia that involves CB₁ and CB₂ cannabinoid receptors. However, there is compelling evidence that Δ⁹-THC can potently inhibit Cav3.2T-type calcium channels which are highly expressed in dorsal root ganglion neurons and in the dorsal horn of the spinal cord. Here, we investigated whether spinal analgesia produced by Δ⁹-THC involves Cav3.2 channels vis a vis cannabinoid receptors. We show that spinally delivered Δ⁹-THC produced dose-dependent and long-lasting mechanical anti-hyperalgesia in neuropathic mice, and showed potent analgesic effects in models of inflammatory pain induced by formalin or Complete Freund's Adjuvant (CFA) injection into the hind paw, with the latter showing no overt sex differences. The Δ⁹-THC mediated reversal of thermal hyperalgesia in the CFA model was abolished in Cav3.2 null mice, but was unaltered in CB₁ and CB₂ null animals. Hence, the analgesic effects of spinally delivered Δ⁹-THC are due to an action on T-type calcium channels, rather than activation of spinal cannabinoid receptors.