Journal Article

Transient receptor potential channels: targeting pain at the source

Patapoutian, Ardem, Tate, Simon, Woolf, Clifford J.

2009

Overview

Key Points The detection of noxious stimuli by nociceptors is mediated by high-threshold transducers expressed on their peripheral terminal membranes. These transducers are receptor/ion channels that convert thermal, mechanical and chemical stimuli into ion fluxes that excite the neuron to produce a sensory inflow. Transient receptor potential (TRP) channels are the most prominent family of nociceptive ion-channel transducer proteins and encode thermal and chemical stimuli. Among the TRP channels expressed by nociceptors, TRPV1 and TRPA1 have been the most extensively investigated, and represent validated targets for the development of novel analgesics. In addition to detecting noxious stimuli, the density, threshold and kinetics of TRPV1 and TRPA1 are modulated by inflammatory mediators, and in this way sensitize nociceptors to increase pain sensitivity after tissue damage or on exposure to inflammation. TRPV1 and TRPA1 are also expressed on the central terminals of sensory neurons where they seem to act as synaptic modulators. Antagonists acting at these two channels are promising candidates as analgesics by virtue of blocking the activation of the channels in response to noxious stimuli or inflammation. TRP nociceptive transducer proteins may have adaptive actions beyond simply detecting noxious stimuli, including body temperature control, synaptic plasticity, and respiratory and cardiovascular function, which may produce adverse effects when blocked. TRP channel agonists can also produce analgesia by either desensitizing the receptors or, at high doses, ablating them. TRP channels can be used as a drug delivery system to target small cationic drugs selectively into nociceptors. Overall, targeting nociceptive TRP channels, where the pain-pathway begins, represents a promising opportunity for the development of novel analgesics. Transient receptor potential (TRP) channels are the most prominent family of nociceptive ion-channel transducer proteins. This Review highlights evidence supporting particular TRP channels as targets for analgesics, indicates the likely efficacy profiles of TRP-channel-acting compounds and looks at recent clinical trials with TRP-channel-acting drugs. Pain results from the complex processing of neural signals at different levels of the central nervous system, with each signal potentially offering multiple opportunities for pharmacological intervention. A logical strategy for developing novel analgesics is to target the beginning of the pain pathway, and aim potential treatments directly at the nociceptors — the high-threshold primary sensory neurons that detect noxious stimuli. The largest group of receptors that function as noxious stimuli detectors in nociceptors is the transient receptor potential (TRP) channel family. This Review highlights evidence supporting particular TRP channels as targets for analgesics, indicates the likely efficacy profiles of TRP-channel-acting drugs, and discusses the development pathways needed to test candidates as analgesics in humans.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: Analgesics - therapeutic use / Animals / Biomedical and Life Sciences / Biomedicine / Biotechnology / Cancer Research / Drug therapy / Humans / Ion channels / Medicinal Chemistry / Molecular Medicine / Neural receptors / Nociceptors - drug effects / Nociceptors - physiology / Pain / Pain - drug therapy / Pain - etiology / Pharmacology / Pharmacology/Toxicology / Physiological aspects / review-article / Transient Receptor Potential Channels - drug effects / Transient Receptor Potential Channels - physiology