title: Antinociceptive effects induced through the stimulation of spinal cannabinoid type 2 receptors in chronically inflamed mice.
abstract: The stimulation of spinal cannabinoid type 2 (CB(2)) receptors is a suitable strategy for the alleviation of experimental pain symptoms. Several reports have described the up-regulation of spinal cannabinoid CB(2) receptors in neuropathic settings together with the analgesic effects derived from their activation. Besides, we have recently reported in two murine bone cancer models that the intrathecal administration of cannabinoid CB(2) receptor agonists completely abolishes hyperalgesia and allodynia, whereas spinal cannabinoid CB(2) receptor expression remains unaltered. The present experiments were designed to measure the expression of spinal cannabinoid CB(2) receptors as well as the analgesic efficacy derived from their stimulation in mice chronically inflamed by the intraplantar injection of complete Freund's adjuvant 1 week before. Both spinal cannabinoid CB(2) receptors mRNA measured by real-time PCR and cannabinoid CB(2) receptor protein levels measured by western blot remained unaltered in inflamed mice. Besides, the intrathecal (i.t.) administration of the cannabinoid CB(2) receptor agonists AM1241, (R,S)-3-(2-Iodo-5-nitrobenzoyl)-1-(1-methyl-2-piperidinylmethyl)-1H-indole, (0.03-1 μg) and JWH 133, (6aR,10aR)-3-(1,1-Dimethylbutyl)-6a,7,10,10a-tetrahydro-6,6,9-trimethyl-6H-dibenzo[b,d]pyran, (3-30 μg) dose-dependently blocked inflammatory thermal hyperalgesia and mechanical allodynia. The analgesic effects induced by both agonists were counteracted by the coadministration of the selective cannabinoid CB(2) receptor antagonist SR144528, 5-(4-chloro-3-methylphenyl)-1-[(4-methylphenyl)methyl]-N-[(1S,2S,4R)-1,3,3-trimethylbicyclo[2.2.1]hept-2-yl]-1H-pyrazole-3-carboxamide, (5 μg) but not by the cannabinoid CB(1) receptor antagonist AM251, N-(Piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide, (10 μg). The effects induced by AM1241 were also inhibited by the coadministration of the opioid receptor antagonist, naloxone (1 μg). These results demonstrate that effective analgesia can be achieved in chronic inflammatory settings through the stimulation of spinal cannabinoid CB(2) receptors even if this receptor population is not up-regulated.
authors.affiliation: Laboratorio de Farmacología, Facultad de Medicina, Instituto Universitario de Oncología del Principado de Asturias, Universidad de Oviedo, Facultad de Medicina C/ Julián Clavería, 6. 33006 Oviedo, Asturias, Spain. curtoverdad.uo@uniovi.es
authors.forename: Verdad
authors.initials: V
authors.lastname: Curto-Reyes
authors.forename: Tamara
authors.initials: T
authors.lastname: Boto
authors.forename: Agustín
authors.initials: A
authors.lastname: Hidalgo
authors.forename: Luis
authors.initials: L
authors.lastname: Menéndez
authors.forename: Ana
authors.initials: A
authors.lastname: Baamonde
mesh_terms: D000700:Analgesics / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D002186:Cannabinoids / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D002908:Chronic Disease / Q000188:drug therapy; D005620:Freund's Adjuvant / Q000009:adverse effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006930:Hyperalgesia / Q000150:complications / Q000188:drug therapy; D007249:Inflammation / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D051379:Mice; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000378:metabolism*; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism*; D013696:Temperature
chemical_list: C439263:AM 1241; D000700:Analgesics; D002186:Cannabinoids; D012333:RNA, Messenger; D043885:Receptor, Cannabinoid, CB2; D005620:Freund's Adjuvant; C432747:1,1-dimethylbutyl-1-deoxy-Delta(9)-THC