title: Spinal anandamide produces analgesia in neuropathic rats: possible CB(1)- and TRPV1-mediated mechanisms.
abstract: The endocannabinoid anandamide (AEA) activates also transient receptor potential vanilloid-1 (TRPV1) channels. However, no data exist on the potential role of spinal TRPV1 activation by AEA in neuropathic pain. We tested the effect of: 1) AEA (5-100 μg), alone or in the presence of an inhibitor of its hydrolysis, and 2) elevated levels of endogenous AEA (following inhibition of AEA hydrolysis), in CCI rats, and the involvement of TRPV1 or cannabinoid CB(1) receptors in the observed effects. Levels of AEA in the spinal cord of CCI rats were measured following all treatments. AEA (50 μg) displayed anti-allodynic and anti-hyperalgesic effects which were abolished by previous antagonism of TRPV1, but not CB(1), receptors. Depending on the administered dose, the selective inhibitor of AEA enzymatic hydrolysis, URB597 (10-100 μg), reduced thermal and tactile nociception via CB(1) or CB(1)/TRPV1 receptors. The anti-nociceptive effects of co-administered per se ineffective doses of AEA (5 μg) and URB597 (5 μg) was abolished by antagonism of CB(1), but not TRPV1, receptors. Spinal AEA levels were increased after CCI, slightly increased further by URB597, 10 μg i.t., and strongly elevated by URB597, 100 μg. Injection of AEA (50 μg) into the lumbar spinal cord led to its dramatic elevation in this tissue, whereas, when a lower dose was used (5 μg) AEA endogenous levels were elevated only in the presence of URB597 (5 μg). We suggest that spinal AEA reduces neuropathic pain via CB(1) or TRPV1, depending on its local concentration.
authors.affiliation: Dept. of Pain Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna str, 31-343 Krakow, Poland.
authors.forename: K
authors.initials: K
authors.lastname: Starowicz
authors.forename: W
authors.initials: W
authors.lastname: Makuch
authors.forename: M
authors.initials: M
authors.lastname: Osikowicz
authors.forename: F
authors.initials: F
authors.lastname: Piscitelli
authors.forename: S
authors.initials: S
authors.lastname: Petrosino
authors.forename: V
authors.initials: V
authors.lastname: Di Marzo
authors.forename: B
authors.initials: B
authors.lastname: Przewlocka
mesh_terms: D000698:Analgesia; D000818:Animals; D001095:Arachidonic Acids / Q000627:therapeutic use*; D063385:Cannabinoid Receptor Modulators / Q000627:therapeutic use*; D063388:Endocannabinoids; D006930:Hyperalgesia / Q000188:drug therapy*; D008297:Male; D009437:Neuralgia / Q000188:drug therapy*; D010147:Pain Measurement / Q000187:drug effects; D053284:Polyunsaturated Alkamides / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism; D012584:Sciatic Nerve / Q000293:injuries*; D050916:TRPV Cation Channels / Q000378:metabolism
chemical_list: D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D053284:Polyunsaturated Alkamides; D043884:Receptor, Cannabinoid, CB1; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; C078814:anandamide