Transient receptor potential (TRP) ion channels have been extensively investigated over the past few years and they are being ardently pursued as targets for drug discovery. Several factors make TRP ion channels appealing as drug targets. First, they are the largest group of noxious stimulus detectors in pain receptors (nociceptors). Second, although pain is currently the most advanced TRP channel-related field, an increasing number of gene deletion researches in animals and genetic association studies in humans have demonstrated that the pathophysiological roles of TRP channels extend well beyond the sensory nervous system (vision, olfaction, taste, mechano- and thermosensation, and osmoregulation). Many studies implicate them in other body systems, including pulmonary, cardiovascular, renal, and bladder systems.
Many TRP channels are expressed by the central nervous system; some are expressed at the spinal cord level (for example TRPA1, TRPM8 and TRPV1 channels), whereas others are expressed at high levels in the cerebrum (e.g., TRPC3 in cerebellar Purkinje cells, and TRPC5 in the hippocampus and amygdala). TRPM2 and TRPM7 are expressed in brain neurons and microglia and are implicated in various pathologies related to oxidative stress, including the focal ischemia model of stroke. Therefore, TRPM7 antagonists may have a role in the treatment of stroke. The TRPM2 gene is also a candidate risk factor gene for bipolar disorder.
Recent findings in the field of pain have established a subset of TRP channels that are activated by temperature (the so-called thermoTRP ion channels) and are capable of initiating sensory nerve impulses following the detection of thermal, as well as mechanical and chemical irritant stimuli. At least, a family of six thermoTRP channels (TRPA1, TRPM8, TRPV1, TRPV2, TRPV3, and TRPV4) exhibits sensitivity to increases or decreases in temperature as well as to chemical substances that elicit similar hot or cold sensations. Such irritants include menthol from mint, cinnamaldehyde, gingerol, capsaicin from chili peppers, mustard oil, camphor, eugenol from cloves, and others.
This review focuses on recent developments in the TRP ion channel-related area and highlights evidence supporting TRP channels as promising targets for new analgesic drugs at the periphery and central levels and opportunities for therapeutic intervention.
Keywords: Allodynia, cold pain, heat pain, sensory neurons, signal transduction, nociception.