TRPA 1 mediates the antinociceptive properties of the constituent of Crocus sativus L., safranal

Safranal, contained in Crocus sativus L., exerts anti‐inflammatory and analgesic effects. However, the underlying mechanisms for such effects are poorly understood. We explored whether safranal targets the transient receptor potential ankyrin 1 ( TRPA 1) channel, which in nociceptors mediates pain signals. Safranal by binding to specific cysteine/lysine residues, stimulates TRPA 1, but not the TRP vanilloid 1 and 4 channels ( TRPV 1 and TRPV 4), evoking calcium responses and currents in human cells and rat and mouse dorsal root ganglion ( DRG ) neurons. Genetic deletion or pharmacological blockade of TRPA 1 attenuated safranal‐evoked release of calcitonin gene‐related peptide ( CGRP ) from rat and mouse dorsal spinal cord, and acute nociception in mice. Safranal contracted rat urinary bladder isolated strips in a TRPA 1‐dependent manner, behaving as a partial agonist. After exposure to safranal the ability of allyl isothiocyanate ( TRPA 1 agonist), but not that of capsaicin ( TRPV 1 agonist) or GSK 1016790A ( TRPV 4 agonist), to evoke currents in DRG neurons, contraction of urinary bladder strips and CGRP release from spinal cord slices in rats, and acute nociception in mice underwent desensitization. As previously shown for other herbal extracts, including petasites or parthenolide, safranal might exert analgesic properties by partial agonism and selective desensitization of the TRPA 1 channel.