Targeting Ca2+ channels to treat pain: T-type versus N-type.

The transmission of pain signals at the spinal level is crucially dependent on voltage-gated Ca2+ channels in nociceptive neurons. Pharmacological and gene-knockout studies implicate N-type Ca2+ channels as key mediators of nociceptive signaling in dorsal root ganglion (DRG) neurons, and as potential targets for the development of analgesic drugs. Furthermore, nociceptor-specific alternative splicing of the gene encoding N-type Ca2+ channels might provide strategies for splice-isoform-specific drug targeting. More recently, T-type Ca2+ channels have been implicated in the processing of pain signals at both spinal and thalamic levels. However, although inhibition of T-type channel activity in DRG neurons mediates analgesia, gene knockout of T-type channels in the CNS is reported to increase the perception of visceral pain. In this review, we discuss the implications of these findings for the design of novel therapeutic strategies and contrast the role of T-type channels with that of N-type channels in pain transmission and analgesia.