Activation and desensitization of TRPV1 channels in sensory neurons by the PPARα agonist palmitoylethanolamide.

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 (Ca²⁺) in peripheral sensory neurons, has been assessed in the present study. The potential involvement of the transcription factor PPARα and of TRPV1 channels in PEA-induced effects was also studied.

EXPERIMENTAL APPROACH

Ca²⁺ was evaluated by single-cell microfluorimetry in differentiated F11 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 F11 cells, PEA (1-30 μM) dose-dependently increased Ca²⁺. The TRPV1 antagonists capsazepine (1 μM) and SB-366791 (1 μM), as well as the PPARα antagonist GW-6471 (10 μM), inhibited PEA-induced Ca²⁺ 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 PPARα. 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 Ca²⁺ transients, as well as CAP-induced TRPV1 activation.

CONCLUSIONS AND IMPLICATIONS

Activation of PPARα and TRPV1 channels, rather than of cannabinoid receptors, largely mediate PEA-induced Ca²⁺ 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.