The endogenous cannabinoid anandamide inhibits transient receptor potential vanilloid type 1 receptor-mediated currents in rat cultured primary sensory neurons.
The activity of the transient receptor potential vanilloid type 1 ion channel (TRPV1) that is expressed by the great majority of polymodal nociceptors is pivotal for the development of inflammatory heat hyperalgesia. The responsiveness of TRPV1 is regulated by a series of intracellular signalling molecules including the cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA); increased or decreased PKA activity results in TRPV1 sensitisation or desensitisation, respectively. Activation of the cannabinoid 1 (CB1) receptor that is expressed by the majority of the TRPV1-expressing primary sensory neurons reduces PKA activity. Therefore, here we studied whether activation of the CB1 receptor resulted in reduced TRPV1-mediated responses in cultured rat primary sensory neurons. We found that TRPV1-mediated whole-cell currents were significantly reduced respectively, by 50% and 25% by 10 nM and 30 nM of the endogenous CB1 receptor agonist, anandamide. The PKA inhibitor, H89 (10 microM) also had a significant inhibitory effect on TRPV1-mediated currents ( approximately 70%). These findings suggest that activation of the CB1 receptor can reduce the activity of TRPV1 in primary sensory neurons, and that this inhibitory effect could be mediated through the reduction of PKA-mediated phosphorylation of TRPV1.
Sántha
P
P
Section of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer Faculty of Medicine, Chelsea and Westminster Hospital, London, UK.
Jenes
A
A
Somogyi
Cs
C
Nagy
Istvan
I
D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism*; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism*; D002211:Capsaicin / Q000494:pharmacology; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D063388:Endocannabinoids; D005071:Evoked Potentials; D005260:Female; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D007546:Isoquinolines / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D010766:Phosphorylation; D053284:Polyunsaturated Alkamides / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000378:metabolism*; D018689:Sensory System Agents / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*
D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D007546:Isoquinolines; D053284:Polyunsaturated Alkamides; D047428:Protein Kinase Inhibitors; D043884:Receptor, Cannabinoid, CB1; D018689:Sensory System Agents; D013449:Sulfonamides; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; D017868:Cyclic AMP-Dependent Protein Kinases; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; D002211:Capsaicin; C078814:anandamide