T-Type Calcium Channels: An Emerging Therapeutic Target for the Treatment of Pain

It has become generally accepted that presynaptic high voltage–activated N-type calcium channels located in the spinal dorsal horn are a validated clinical target for therapeutic interventions associated with severe intractable pain. Low voltage–activated (T-type) calcium channels play a number of critical roles in nervous system function, including controlling thalamocortical bursting behaviours and the generation of spike wave discharges associated with slow wave sleep patterns. There is a growing body of evidence that T-type calcium channels also contribute in several ways to both acute and neuropathic nociceptive behaviours. In the one instance, the Cav3.1 T-type channel isoform likely contributes an antinociceptive function in thalamocortical central signalling, possibly through the activation of inhibitory nRT neurons. In another instance, the Cav3.2 T-type calcium channel subtype acts at the level of primary afferents in a strongly pro-nociceptive manner in both acute and neuropathic models. While a number of classes of existing clinical agents non-selectively block T-type calcium channels, there are no subtypespecific drugs yet available. The development of agents selectively targeting peripheral Cav3.2 T-type calcium channels may represent an attractive new avenue for therapeutic intervention. Drug Dev. Res. 67:404–415, 2006. c 2006 Wiley-Liss, Inc.