The discovery that the capacity to detect many forms of noxious stimuli is mediated by high-threshold TRP channels expressed selectively in nociceptors has provided insights into the molecular basis of sensory labelled lines — neural input channels devoted to specific types of stimuli and in the peripheral nervous system. It has also provided an opportunity for the development of analgesics that are different from the non-steroidal anti-inflammatory drugs, opiates, anticonvulsants and antidepressants currently used.
The field has moved relatively quickly, from the cloning of TRPV1 to clinical trials within 10 years. Studies on TRPV1 raise the intriguing possibility that these ion channels have functional roles greater than initially anticipated, which may provide problems and opportunities. For example, while TRPV1 is an acute noxious heat receptor, it also seems to be a major player in various pain states such as bone cancer pain and neuropathic pain, as well as in thermoregulation and hippocampal plasticity. TRPA1 also seems to be a major player is sensing damage, and has great clinical potential as an analgesic and perhaps even more so for several respiratory diseases.
However, more studies are required to identify which TRP channels will be appropriate targets for which specific pain and other indications. Armed with genetic deletions for each of these ion channels, and specific small-molecule agonists and antagonists against many of them, the important questions should be addressed in the next few years.
We are poised to discover whether drugs that act on sensory TRP channels provide greater efficacy and fewer adverse effects in the treatment of pain than the currently available analgesics. In addition to targeting TRP channels with agonists to activate, desensitize and ablate nociceptors, and with antagonists to reduce TRP activity in the periphery and CNS, we can also use TRP channels as a drug delivery system to target, with TRP agonists, small cationic compounds selectively into those specific cells that express these ion channels. It seems likely that somehow, from these multiple and diverse therapeutic opportunities, TRP channels will provide a new means of reducing pain.