title: Activation of CB1 inhibits NGF-induced sensitization of TRPV1 in adult mouse afferent neurons.
abstract: Transient receptor potential vanilloid 1 (TRPV1)-containing afferent neurons convey nociceptive signals and play an essential role in pain sensation. Exposure to nerve growth factor (NGF) rapidly increases TRPV1 activity (sensitization). In the present study, we investigated whether treatment with the selective cannabinoid receptor 1 (CB1) agonist arachidonyl-2'-chloroethylamide (ACEA) affects NGF-induced sensitization of TRPV1 in adult mouse dorsal root ganglion (DRG) afferent neurons. We found that CB1, NGF receptor tyrosine kinase A (trkA), and TRPV1 are present in cultured adult mouse small- to medium-sized afferent neurons and treatment with NGF (100ng/ml) for 30 min significantly increased the number of neurons that responded to capsaicin (as indicated by increased intracellular Ca(2 +) concentration). Pretreatment with the CB1 agonist ACEA (10nM) inhibited the NGF-induced response, and this effect of ACEA was reversed by a selective CB1 antagonist. Further, pretreatment with ACEA inhibited NGF-induced phosphorylation of AKT. Blocking PI3 kinase activity also attenuated the NGF-induced increase in the number of neurons that responded to capsaicin. Our results indicate that the analgesic effect of CB1 activation may in part be due to inhibition of NGF-induced sensitization of TRPV1 and also that the effect of CB1 activation is at least partly mediated by attenuation of NGF-induced increased PI3 signaling.
authors.affiliation: Department of Surgical Sciences, University of Wisconsin-Madison, United States. Electronic address: wangz@svm.vetmed.wisc.edu.
authors.forename: Z-Y
authors.initials: ZY
authors.lastname: Wang
authors.affiliation: Department of Anesthesiology, University of Wisconsin-Madison, United States.
authors.forename: T
authors.initials: T
authors.lastname: McDowell
authors.affiliation: Department of Surgical Sciences, University of Wisconsin-Madison, United States.
authors.forename: P
authors.initials: P
authors.lastname: Wang
authors.affiliation: Department of Obstetrics & Gynecology, University of Wisconsin-Madison, United States.
authors.forename: R
authors.initials: R
authors.lastname: Alvarez
authors.affiliation: Department of Neuroscience, University of Wisconsin-Madison, United States.
authors.forename: T
authors.initials: T
authors.lastname: Gomez
authors.affiliation: Department of Surgical Sciences, University of Wisconsin-Madison, United States; Department of Urology, University of Wisconsin-Madison, United States.
authors.forename: D E
authors.initials: DE
authors.lastname: Bjorling
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D063386:Cannabinoid Receptor Agonists / Q000494:pharmacology; D002211:Capsaicin / Q000494:pharmacology; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000187:drug effects / Q000502:physiology*; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D020932:Nerve Growth Factor / Q000378:metabolism*; D009475:Neurons, Afferent / Q000187:drug effects / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000378:metabolism*; D020917:Receptor, trkA / Q000378:metabolism*; D018689:Sensory System Agents / Q000494:pharmacology; D050916:TRPV Cation Channels / Q000378:metabolism*
chemical_list: D001095:Arachidonic Acids; D002118:Calcium; D063386:Cannabinoid Receptor Agonists; D002211:Capsaicin; D004791:Enzyme Inhibitors; D020932:Nerve Growth Factor; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D043884:Receptor, Cannabinoid, CB1; D020917:Receptor, trkA; D018689:Sensory System Agents; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; C119325:arachidonyl-2-chloroethylamide
keywords: cannabinoid receptor 1; capsaicin; nerve growth factor; phosphorylation of AKT; sensitization; transient receptor potential vanilloid 1
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