The cannabinoid 1 receptor antagonist AM251 produces nocifensive behavior via activation of ERK signaling pathway.
Intrathecal (i.t.) injection of AM251, a cannabinoid 1 (CB(1)) receptor antagonist, into the spinal lumbar space of mice elicited a behavioral response consisting of biting and licking with a few scratchings. In this study, we investigated to determine whether i.t. AM251 could influence the activity of extracellular signal-regulated kinase-1 and -2 (ERK1/2), a mitogen-activated protein kinase (MAPK) in neuronal nitric oxide synthase (nNOS) and inducible NOS (iNOS) activation. The CB(1) receptor agonist ACEA, neurokinin 1 (NK(1)) receptor antagonists and NMDA receptor antagonists, inhibited i.t. AM251-induced behavioral response in a dose-dependent manner. The CB(2) receptor agonist, JWH-133 gave no effect on response elicited by i.t. AM251. Both non-selective NOS inhibitors, L-NAME and 7-NI, and N(ω)-propyl-L-arginine, a selective inhibitor of nNOS resulted in a dose-dependent inhibition of i.t. AM251-induced behavioral response. The selective iNOS inhibitor, 1400W, in relatively large doses, inhibited in a non dose-dependent manner. The i.t. injection of AM251 produced a definite activation of ERK1/2 in the lumbar dorsal spinal cord. Behavioral experiments showed that U0126, a MAPK/ERK kinase (MEK) inhibitor, dose-dependently attenuated the behavioral response to i.t. AM251. Spinal activation of ERK1/2 following i.t. AM251 was reduced clearly by N(ω)-propyl-L-arginine and U0126, while 1400W gave a significant effect on only ERK1 activation. These findings suggest that the nNOS-ERK pathway in spinal cord neurones plays an important role in AM251-induced nocifensive behavior and its inhibition may provide significant anti-nociception.
Katsuyama
Soh
S
First Department of Pharmacology, Daiichi College of Pharmaceutical Sciences, 22-1 Tamagawa-cho, Minami-ku, Fukuoka 815-8511, Japan.
Mizoguchi
Hirokazu
H
Komatsu
Takaaki
T
Nagaoka
Kohshi
K
Sakurada
Shinobu
S
Sakurada
Tsukasa
T
D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D015153:Blotting, Western; D063387:Cannabinoid Receptor Antagonists; D004305:Dose-Response Relationship, Drug; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D007278:Injections, Spinal; D008297:Male; D051379:Mice; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D010147:Pain Measurement / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D043882:Receptors, Cannabinoid / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism
D063387:Cannabinoid Receptor Antagonists; D010880:Piperidines; D011720:Pyrazoles; D043882:Receptors, Cannabinoid; C103505:AM 251; D052248:Nitric Oxide Synthase Type I; D048049:Extracellular Signal-Regulated MAP Kinases