Functional and biochemical interaction between PPARα receptors and TRPV1 channels: Potential role in PPARα agonists-mediated analgesia

Transient receptor potential vanilloid type-1 (TRPV1) channels expressed in primary afferent neurons play a critical role in nociception triggered by endogenous and exogenous compounds. In the present study, the functional and biochemical interaction between TRPV1 channels and type-a peroxisome proliferator-activated receptors (PPAR alpha) has been investigated. In TRPV1-expressing CHO cells, patch clamp studies revealed that acute application of the PPARa agonists clofibrate (CLO; 0.1-100 mu M), WY14643 (1-300 mu M), or GW7647 (0.1-100 nM) activated TRPV1 currents in a concentration-dependent manner, with EC50s of 53 +/- 0.8 mu M, 13.0 +/- 1.2 mu M, and 12.7 +/- 0.3 nM, respectively. The role of PPARa in these pharmacological responses was confirmed by the ability of the PPARa antagonist GW6471 (10 mu M) to block CLO-, WY14643- and GW7647-induced TRPV1 activation, and by the observation that modulation of PPARa levels via siRNA-mediated suppression or PPARa over-expression affected TRPV1 channel activation by PPARa agonists accordingly. In cells cotransfected with PPARa and TRPV1, PPARa receptors were detected in TRPV1-immunoprecipitated fractions. When compared to capsaicin (CAP), TRPV1 currents activated by PPARa agonists showed a higher degree of acute desensitization and tachyphylaxis; moreover, GW7647, when pre-incubated at a concentration (1 nM) unable to activate TRPV1 currents per se, desensitized CAP-induced TRPV1 currents. Finally, a sub-effective concentration of each PPARa agonist inhibited TRPV1-dependent bradykinin-induced [Ca2+] transients in sensory neurons. Collectively, these results provide evidence for a PPAR alpha-mediated pathway triggering TRPV1 channel activation and desensitization, and highlight a novel mechanism which might contribute to the analgesic effects shown by PPARa agonists in vivo. 2014 Elsevier Ltd. All rights reserved.