Proceedings of The Physiological Society

Cardiff University (2009) Proc Physiol Soc 17, PC37

Poster Communications

Mechanisms of TRPV1-mediated desensitisation of the nociceptive ion channel, TRPA1

C. Doran1, G. Reid1

1. Department of Physiology, University College Cork, Cork, Ireland.

Transient receptor potential A1 (TRPA1) is an ion channel receptor that specifically responds to noxious compounds such as cinnamaldehyde and bradykinin. TRPA1 is thought to be involved in various pain pathways, including cold allodynia and mechanical hyperalgesia. It is co-expressed with the capsaicin receptor, TRPV1, in primary sensory neurones. We have previously reported that activation of TRPV1 leads to a desensitisation of TRPA1, through a calcium-dependent mechanism. Here, we further the case for the involvement of elevated [Ca2+]i in TRPA1 inhibition and uncover the role of other second messengers that act downstream of TRPV1 activation. Adult Sprague-Dawley rats were killed by 100 % CO2 inhalation followed by decapitation, and dissociated DRG neurones cultured with nerve growth factor for 12-24 hours. Responses of individual neurones to all compounds were evaluated using Calcium Green-1 microfluorimetry (ΔF/F0). Previously, we have shown that 1 μM capsaicin and 50mM KCL elicit comparable rises in [Ca2+]i in TRPV1 positive neurones and that in both cases this leads to a desensitisation of TRPA1. We now further report that TRPA1 responsiveness to cinnamaldehyde (200 μM) remains intact following activation of TRPV1 by capsaicin (1 μM) in reduced [Ca2+]i conditions. In nominally calcium-free extracellular solution, the response to cinnamaldehyde was reduced (by 30 %), but not abolished, by preceding application of capsaicin. We conclude that calcium is a crucial second messenger involved in TRPV1-mediated inhibition of TRPA1. We propose that pharmacological targeting of second messengers could be a potential avenue for blunting TRPA1-mediated nociception.

Where applicable, experiments conform with Society ethical requirements