title: Antinociceptive effects of the selective CB2 agonist MT178 in inflammatory and chronic rodent pain models.
abstract: Cannabinoid CB(2) receptor activation by selective agonists has been shown to produce analgesic effects in preclinical models of inflammatory, neuropathic, and bone cancer pain. In this study the effect of a novel CB(2)agonist (MT178) was evaluated in different animal models of pain. First of all, in vitro competition binding experiments performed on rat, mouse, or human CB receptors revealed a high affinity, selectivity, and potency of MT178. The analgesic properties of the novel CB(2) agonist were evaluated in various in vivo experiments, such as writhing and formalin assays, showing a good efficacy comparable with that produced by the nonselective CB agonist WIN 55,212-2. A dose-dependent antiallodynic effect of the novel CB(2) compound in the streptozotocin-induced diabetic neuropathy was found. In a bone cancer pain model and in the acid-induced muscle pain model, MT178 was able to significantly reduce mechanical hyperalgesia in a dose-related manner. Notably, MT178 failed to provoke locomotor disturbance and catalepsy, which were observed following the administration of WIN 55,212-2. CB(2) receptor mechanism of action was investigated in dorsal root ganglia where MT178 mediated a reduction of [(3)H]-d-aspartate release. MT178 was also able to inhibit capsaicin-induced substance P release and NF-κB activation. These results demonstrate that systemic administration of MT178 produced a robust analgesia in different pain models via CB(2) receptors, providing an interesting approach to analgesic therapy in inflammatory and chronic pain without CB(1)-mediated central side effects.
authors.affiliation: Department of Clinical and Experimental Medicine, Pharmacology Section, University of Ferrara, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Vincenzi
authors.forename: Martina
authors.initials: M
authors.lastname: Targa
authors.forename: Carmen
authors.initials: C
authors.lastname: Corciulo
authors.forename: Mojgan Aghazadeh
authors.initials: MA
authors.lastname: Tabrizi
authors.forename: Stefania
authors.initials: S
authors.lastname: Merighi
authors.forename: Stefania
authors.initials: S
authors.lastname: Gessi
authors.forename: Giulia
authors.initials: G
authors.lastname: Saponaro
authors.forename: Pier Giovanni
authors.initials: PG
authors.lastname: Baraldi
authors.forename: Pier Andrea
authors.initials: PA
authors.lastname: Borea
authors.forename: Katia
authors.initials: K
authors.lastname: Varani
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D059350:Chronic Pain / Q000188:drug therapy* / Q000378:metabolism; D003929:Diabetic Neuropathies / Q000188:drug therapy* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy* / Q000378:metabolism; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D059352:Musculoskeletal Pain / Q000188:drug therapy* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010078:Oxazines / Q000819:agonists*; D010147:Pain Measurement; D015363:Quinolones / Q000819:agonists*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists*; D045442:Rotarod Performance Test; D016896:Treatment Outcome
chemical_list: C585447:N-adamantyl-3-ethyl-3,7-dihydro-7-oxo-10-(pyrrolidin-1-yl)-2H-(1,4)oxazino(2,3,4-ij)quinoline-6-carboxamide; D016328:NF-kappa B; D010078:Oxazines; D015363:Quinolones; D043885:Receptor, Cannabinoid, CB2