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Pharmacol Res. 2014 Sep;87:113-22. doi: 10.1016/j.phrs.2014.06.015. Epub 2014 Jul 8.

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

Author information

1
Dept. of Medicine and Health Sciences, University of Molise, Campobasso, Italy. Electronic address: paolo.ambrosino@unimol.it.
2
Dept. of Medicine and Health Sciences, University of Molise, Campobasso, Italy. Electronic address: mariavirginia.soldovieri@unimol.it.
3
Dept. of Medicine and Health Sciences, University of Molise, Campobasso, Italy. Electronic address: michela.demaria@studenti.unimol.it.
4
Dept. of Medicine and Health Sciences, University of Molise, Campobasso, Italy. Electronic address: claudio.russo@unimol.it.
5
Dept. of Medicine and Health Sciences, University of Molise, Campobasso, Italy; Dept. of Neuroscience, Section of Pharmacology, University of Naples Federico II, Naples, Italy. Electronic address: m.taglialatela@unimol.it.

Abstract

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-α peroxisome proliferator-activated receptors (PPARα) has been investigated. In TRPV1-expressing CHO cells, patch-clamp studies revealed that acute application of the PPARα agonists clofibrate (CLO; 0.1-100 μM), WY14643 (1-300 μM), or GW7647 (0.1-100 nM) activated TRPV1 currents in a concentration-dependent manner, with EC50s of 5.3 ± 0.8 μM, 13.0 ± 1.2 μM, and 12.7 ± 0.3 nM, respectively. The role of PPARα in these pharmacological responses was confirmed by the ability of the PPARα antagonist GW6471 (10 μM) to block CLO-, WY14643- and GW7647-induced TRPV1 activation, and by the observation that modulation of PPARα levels via siRNA-mediated suppression or PPARα over-expression affected TRPV1 channel activation by PPARα agonists accordingly. In cells cotransfected with PPARα and TRPV1, PPARα receptors were detected in TRPV1-immunoprecipitated fractions. When compared to capsaicin (CAP), TRPV1 currents activated by PPARα agonists showed a higher degree of acute desensitization and tachyphylaxis; moreover, GW7647, when pre-incubated at a concentration (1nM) unable to activate TRPV1 currents per se, desensitized CAP-induced TRPV1 currents. Finally, a sub-effective concentration of each PPARα agonist inhibited TRPV1-dependent bradykinin-induced [Ca(2+)]i transients in sensory neurons. Collectively, these results provide evidence for a PPARα-mediated pathway triggering TRPV1 channel activation and desensitization, and highlight a novel mechanism which might contribute to the analgesic effects shown by PPARα agonists in vivo.

KEYWORDS:

Analgesic effects; Bradykinin; Channel activation and desensitization; Primary sensory neurons; Transient receptor potential vanilloid type-1 (TRPV1) channels; Type-α peroxisome proliferator-activated receptors (PPARα)

PMID:
25014183
DOI:
10.1016/j.phrs.2014.06.015
[Indexed for MEDLINE]

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