NSAIDs Attenuate TRP Channels Activated by their Agonists

Abstract

Background. The transient receptor potential (TRP) cation channels have been extensively investigated in the transduction of thermal, mechanical, and chemical stimuli underlying the somatic sensation. These channels are the largest group of sensory detector proteins expressed in nerve terminals and pain receptors and are activated by temperature and chemicals that elicit hot or cold sensations. Chemical stimuli include menthol, cinnamaldehyde (CA), gingerol, capsaicin (CAPS), allyl isothiocyanate (AITC) (a natural compound of mustard oil), camphor, eugenol, and others. The thermal thresholds of many TRP channels are known to be modulated by extracellular mediators and released by tissue damage or inflammation, such as bradykinin, prostaglandins, and growth factors. Antagonists of these channels are likely promising targets for new analgesic drugs at the peripheral and central levels.

Aims. Because some non-steroidal anti-inflammatory drugs (NSAIDs) are structural analogs of prostaglandins, here we examined three widely used NSAIDs (diclofenac, ketorolac, and lornoxicam) on the activation of TRPA1 and TRPV1 channels by their agonists CA, AITC, and CAPS, respectively.

Material and Methods. We measured nociceptive thermal paw withdrawal latencies and mechanical thresholds bilaterally in male rats at various time points following intraplantar injection of CA, AITC, CAPS, producing thermal hyperalgesia and mechanical allodynia, and of NSAIDs and TRP channels antagonists.

Results. We found that intraplantar injection CA, AITC, and CAPS significantly decreased the latency of the thermal withdrawal reflex (thermal hyperalgesia) compared to vehicle or the contralateral hindpaw. The same findings were observed for the paw withdrawal threshold (mechanical allodynia) and hence resulted in the facilitation of these defenses reflexes. In approximately two hours the effects of CA, AITC, and CAPS returned to baseline. Pretreatment with all three NSAIDs in the ipsilateral (injected) hindpaw produced a significant reduction of sensitivity to pain (antinociception). In other experiments, when pretreated with the TRPA1 antagonist (HC-030031) we found a significant attenuation of thermal hyperalgesia and mechanical allodynia evoked by CA and AITC. In the second session, pretreatment with the TRPV1 antagonist (AMG-517) produced a significant reduction of these pain behavior responses.

Conclusion.  Our data clearly show that noxious chemical irritants (CA, AITC, CAPS) eliciting thermal hyperalgesia and mechanical allodynia are mediated via the activation of TRPA1 and TRPV1 cation channels. We suggest that our study indicates a novel mechanism involving the anti-inflammatory and analgesic effects of NSAIDs, which may be involved in direct inactivation or desensitization of TRPA1 and TRPV1 channels and could be used therapeutically for pain treatment.

Acknowledgment.  The work was supported partially by the grant from Shota Rustaveli National Science Foundation of Georgia (SRNSF) (grant #31-40).