Extracellular signal-regulated kinase (ERK) and nitric oxide synthase mediate intrathecal morphine-induced nociceptive behavior.
Intrathecal (i.t.) administration of morphine at a high dose of 60nmol into the spinal lumbar space in mice produces a severe hindlimb scratching followed by biting and licking. Nitric oxide (NO) is thought to play an important role in signal transduction pathways that enhance nociceptive transmission in the spinal cord. The present study was designed to determine whether high-dose i.t. morphine could influence the activation of the extracellular signal-regulated kinase (ERK), a mitogen-activated protein (MAP) kinase in neuronal nitric oxide synthase (nNOS) and inducible NOS (iNOS) activation. Both 7-NI and TRIM, selective inhibitors of nNOS, resulted in a dose-dependent inhibition of high-dose i.t. morphine-induced behavior. The selective iNOS inhibitor W1400 in relatively large doses inhibited in a non dose-dependent manner. The i.t. injection of morphine evoked a definite activation of ERK in the lumbar dorsal spinal cord. Behavioral experiments showed that U0126 (0.5-2.5nmol), a MAP kinase-ERK inhibitor, dose-dependently attenuated the behavioral response to i.t. morphine. In mice treated with high-dose morphine, 7-NI was very effective in blocking ERK activation, whereas W1400 had no effect. Taken together, these results suggest that the behavioral response to high-dose i.t. morphine may be triggered by the nNOS-ERK pathway in the dorsal spinal cord.
Komatsu
Takaaki
T
Department of Biochemistry, Daiichi College of Pharmaceutical Sciences, 22-1 Tamagawa-cho, Minami-ku, Fukuoka 815-8511, Japan.
Sakurada
Chikai
C
Sasaki
Mika
M
Sanai
Kengo
K
Tsuzuki
Minoru
M
Bagetta
Giacinto
G
Sakurada
Shinobu
S
Sakurada
Tsukasa
T
D000578:Amidines / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001596:Benzylamines / Q000494:pharmacology; D015153:Blotting, Western; D002070:Butadienes / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007191:Indazoles / Q000494:pharmacology; D007278:Injections, Spinal; D008297:Male; D051379:Mice; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D009619:Nociceptors / Q000187:drug effects*; D010146:Pain / Q000523:psychology*; D015398:Signal Transduction / Q000187:drug effects
D000578:Amidines; D000701:Analgesics, Opioid; D001596:Benzylamines; D002070:Butadienes; D004791:Enzyme Inhibitors; D007191:Indazoles; C104820:N-(3-(aminomethyl)benzyl)acetamidine; D009570:Nitriles; C113580:U 0126; D009020:Morphine; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D048049:Extracellular Signal-Regulated MAP Kinases; C080122:7-nitroindazole; D019331:NG-Nitroarginine Methyl Ester