TRANSIENT RECEPTOR POTENTIALS OF TRPV1 AND TRPA1 AS TARGETS FOR ANALGESICS ON NOCICEPTORS
Szolcsányi J. Tékus V., Helyes Zs. and Pintér E.
University of Pécs Medical School Department of Pharmacology and Pharmacotherapy, H-7622 Pécs, Szigeti u. 12
Cloning of the transient receptor potentials of vanilloid type (TRPV1), the noxious heat-gated cation channel and the noxious cold-gated ankyrin-type (TRPA1) coexpressed in nociceptive neurons has opened the door for development of novel classes of analgesics (1). Both types of cation channels are sensitive to exogenous and endogenous pain producing agents as TRPV1 to capsaicin, protons and lipoxygenase metabolites, TRPA1 to mustard oil or 4-hydroxy-2-nonenal. Thermosensation and mustard oil-induced hyperalgesia were determined in TRPV1 and TRPA1 gene-deleted mice. On TRPV1-/- mice noxious heat threshold (NHT) was elevated on the tail but not on the paw. Mustard oil-induced fall in NHT was decreased on TRPV1-/- but not on TRPA1-/- mice, while noxious cold sensation was inhibited in TRPA1-/- but not on TRPV1-/- mice. Tail flick evoked by mustard oil was inhibited in both types of gene-deleted mice. It is concluded, that mustard oil influences gating of both TRPV1 and TRPA1 channels and using our novel approach of NHT method impaired noxious heat sensation was revealed for the first time in TRPV1-/- mice similarly as observed in humans with some TRPV1 antagonists as on-target side effect. Cooperation between the two TRP channels and their multisteric operation on polymodal nociceptors is important for further drug development.