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

Br J Pharmacol. 2013 Mar;168(6):1430-44. doi: 10.1111/bph.12029.


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⁺](i)) 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⁺](i) 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⁺](i). 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⁺](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 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⁺](i) 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⁺](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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects
  • Amides
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / antagonists & inhibitors
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • CHO Cells
  • Calcium Signaling / drug effects
  • Cell Line
  • Cricetinae
  • Cricetulus
  • Drug Antagonism
  • Endocannabinoids / antagonists & inhibitors
  • Endocannabinoids / pharmacology*
  • Ethanolamines / antagonists & inhibitors
  • Ethanolamines / pharmacology*
  • Membrane Transport Modulators / antagonists & inhibitors
  • Membrane Transport Modulators / pharmacology
  • Mice
  • Nerve Tissue Proteins / agonists*
  • Nerve Tissue Proteins / antagonists & inhibitors
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • PPAR alpha / agonists*
  • PPAR alpha / antagonists & inhibitors
  • PPAR alpha / metabolism
  • Palmitic Acids / antagonists & inhibitors
  • Palmitic Acids / pharmacology*
  • Rats
  • Recombinant Proteins / agonists
  • Recombinant Proteins / antagonists & inhibitors
  • Recombinant Proteins / metabolism
  • Sensory Receptor Cells / cytology
  • Sensory Receptor Cells / drug effects*
  • Sensory Receptor Cells / metabolism
  • TRPV Cation Channels / agonists*
  • TRPV Cation Channels / antagonists & inhibitors
  • TRPV Cation Channels / genetics
  • TRPV Cation Channels / metabolism
  • Tachyphylaxis*


  • Amides
  • Anti-Inflammatory Agents, Non-Steroidal
  • Endocannabinoids
  • Ethanolamines
  • Membrane Transport Modulators
  • Nerve Tissue Proteins
  • PPAR alpha
  • Palmitic Acids
  • Recombinant Proteins
  • TRPV Cation Channels
  • TRPV1 protein, mouse
  • Trpv1 protein, rat
  • palmidrol