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Activation and desensitization of TRPV1 channels in sensory neurons by the PPARα agonist palmitoylethanolamide
Author(s) -
Ambrosino Paolo,
Soldovieri Maria Virginia,
Russo Claudio,
Taglialatela Maurizio
Publication year - 2013
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.12029
Subject(s) - palmitoylethanolamide , capsazepine , trpv1 , chemistry , desensitization (medicine) , agonist , receptor , cannabinoid receptor , capsaicin , cannabinoid , pharmacology , transient receptor potential channel , microbiology and biotechnology , biochemistry , biology
Background and Purpose Palmitoylethanolamide ( PEA ) is an endogenous fatty acid amide displaying anti‐inflammatory and analgesic actions. To investigate the molecular mechanism responsible for these effects, the ability of PEA and of pain‐inducing stimuli such as capsaicin ( CAP ) or bradykinin ( BK ) to influence intracellular calcium concentrations ([ Ca 2+ ] i ) in peripheral sensory neurons, has been assessed in the present study. The potential involvement of the transcription factor PPAR α and of TRPV1 channels in PEA ‐induced effects was also studied. Experimental Approach [ Ca 2+ ] i was evaluated by single‐cell microfluorimetry in differentiated F 11 cells. Activation of TRPV1 channels was assessed by imaging and patch‐clamp techniques in CHO cells transiently‐transfected with rat TRPV1 cDNA . Key Results In F 11 cells, PEA (1–30 μ M ) dose‐dependently increased [ Ca 2+ ] i . The TRPV1 antagonists capsazepine (1 μ M ) and SB ‐366791 (1 μ M ), as well as the PPAR α antagonist GW ‐6471 (10 μ M ), inhibited PEA ‐induced [ Ca 2+ ] i increase; blockers of cannabinoid receptors were ineffective. PEA activated TRPV1 channels heterologously expressed in CHO cells; this effect appeared to be mediated at least in part by PPAR α. When compared with CAP , PEA showed similar potency and lower efficacy, and caused stronger TRPV1 currents desensitization. Sub‐effective PEA concentrations, closer to those found in vivo , counteracted CAP ‐ and BK ‐induced [ Ca 2+ ] i transients, as well as CAP ‐induced TRPV1 activation. Conclusions and Implications Activation of PPAR α and TRPV1 channels, rather than of cannabinoid receptors, largely mediate PEA ‐induced [ Ca 2+ ] i transients in sensory neurons. Differential TRPV1 activation and desensitization by CAP and PEA might contribute to their distinct pharmacological profile, possibly translating into potentially relevant clinical differences.