TRPA1 as an analgesic target
Humans have cultivated chili peppers for over 5,000 years. For more than 1,000 years extracts from these plants have been used medicinally in the treatment of various forms of pain. As a result, pain researchers have had a long- standing interest in the molecular identity of the receptor for capsaicin, the chemical that produces the sensation of heat from “hot” peppers. When the Julius lab published that TRPV1 is the protein that confers capsaicin responsiveness , there was already significant investigation of this target in the pharmaceutical community. The future of TRPV1 as an analgesic target is currently uncertain because inhibiting TRPV1 attenuates patients' ability to sense damaging heat [2, 3] and because concerns have arisen that TRPV1 antagonists cause a transient hyperthermia. However, this interest in TRPV1 has spurred interest in a variety of other TRP channels in the pain area. As the receptor for mustard oil and other noxious compounds that cause pain, TRPA1 in particular has emerged as a promising target. Recent data suggest that TRPA1 is a broad chemosensor, activated by reactive chemicals that are encountered exogenously and by compounds such as hydrogen peroxide that are endogenously produced during inflammation or tissue damage. In this review, we explore the rationale surrounding the use of TRPA1 as an analgesic target and discuss the unique challenges that face those developing antagonists.