title: CB1 cannabinoid receptor agonist prevents NGF-induced sensitization of TRPV1 in sensory neurons.
abstract: The transient receptor potential vanilloid type 1 channel (TRPV1) and nerve growth factor (NGF) are important mediators of inflammatory pain. NGF released during inflammation sensitizes TRPV1 in afferent nerve endings of peripheral nociceptors, increasing pain sensation. Cannabinoids, by activating CB1 G protein-coupled receptors, produce analgesia in a variety of pain models, though the exact mechanisms are not known. We tested the hypothesis that activation of the CB1 receptor by cannabinoids attenuates NGF-induced TRPV1 sensitization. TRPV1-mediated currents were measured in acutely isolated primary sensory neurons with the whole-cell patch clamp technique using capsaicin (100 nM) as the agonist. After the first capsaicin application, during which the baseline current was measured, cells were exposed to NGF (100 ng/mL), and the capsaicin application was repeated after 5 min. NGF sensitized TRPV1 in 31.0% of cells (13 of 42), with a mean (±SE) increase in the capsaicin-induced current of 262 ± 47% over the baseline current. When the cannabinoid agonist ACEA (arachidonoyl-2'-chloroethylamide; 10nM) was given before NGF, only 10.8% of cells (4 of 37) were sensitized (p<0.05). Neither this rate, nor the magnitude of the sensitization (198 ± 63% of baseline) were different from that seen in cells not treated with NGF (3 of 25 cells sensitized (12.0%), 253 ± 70% of baseline). Pretreatment with the CB1 antagonist AM-251 (100 nM) prevented the effect of ACEA on NGF-induced sensitization. These results support the hypothesis that cannabinoids, acting through CB1 receptors, may produce analgesia in part by preventing NGF-induced sensitization of TRPV1 in afferent nociceptor nerve endings.
authors.affiliation: Department of Anesthesiology, School of Medicine and Public Health, University of Wisconsin-Madison, 600 Highland Avenue, Madison, WI 53792-3272, USA. tsmcdowe@wisc.edu
authors.forename: Thomas S
authors.initials: TS
authors.lastname: McDowell
authors.forename: Zun-Yi
authors.initials: ZY
authors.lastname: Wang
authors.forename: Ruchira
authors.initials: R
authors.lastname: Singh
authors.forename: Dale
authors.initials: D
authors.lastname: Bjorling
mesh_terms: D000818:Animals; D063388:Endocannabinoids / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism*; D020932:Nerve Growth Factor / Q000494:pharmacology*; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists*; D050916:TRPV Cation Channels / Q000378:metabolism*
chemical_list: D063388:Endocannabinoids; D043884:Receptor, Cannabinoid, CB1; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; C561029:arachidonoyl-2 chloroethanolamine; D020932:Nerve Growth Factor
keywords: Analgesia; Cannabinoids; NGF; Nociceptor; Patch clamp; TRPV1