Spinal ERK activation via NO-cGMP pathway contributes to nociceptive behavior induced by morphine-3-glucuronide.
Intrathecal (i.t.) injection of morphine-3-glucuronide (M3G), a major metabolite of morphine without analgesic actions, produces a severe hindlimb scratching followed by biting and licking in mice. The pain-related behavior evoked by M3G was inhibited dose-dependently by i.t. co-administration of tachykinin NK(1) receptor antagonists, sendide, [D-Phe(7), D-His(9)] substance P(6-11), CP-99994 or RP-67580 and i.t. pretreatment with antiserum against substance P. The competitive NMDA receptor antagonists, D-APV and CPP, the NMDA ion-channel blocker, MK-801 or the competitive antagonist of the polyamine recognition site of NMDA receptor ion-channel complex, ifenprodil, produced inhibitory effects on i.t. M3G-evoked nociceptive response. The NO-cGMP-PKG pathway, which involves the extracellular signal-regulated kinase (ERK), has been implicated as mediators of plasticity in several pain models. Here, we investigated whether M3G could influence the ERK activation in the NO-cGMP-PKG pathway. The i.t. injection of M3G evoked a definite activation of ERK in the lumbar dorsal spinal cord, which was prevented dose-dependently by U0126, a MAP kinase-ERK inhibitor. The selective nNOS inhibitor N(omega)-propyl-l-arginine, the selective iNOS inhibitor W1400, the soluble guanylate cyclase inhibitor ODQ and the PKG inhibitor KT-5823 inhibited dose-dependently the nociceptive response to i.t. M3G. In western blotting analysis, inhibiting M3G-induced nociceptive response using these inhibitors resulted in a significant blockade of ERK activation induced by M3G in the spinal cord. Taken together, these results suggest that activation of the spinal ERK signaling in the NO-cGMP-PKG pathway contributes to i.t. M3G-evoked nociceptive response.
Komatsu
Takaaki
T
First Department of Pharmacology, Daiichi College of Pharmaceutical Sciences, 22-1 Tamagawa-cho, Minami-ku, Fukuoka 815-8511, Japan.
Sakurada
Shinobu
S
Kohno
Kazuhiro
K
Shiohira
Hideo
H
Katsuyama
Sou
S
Sakurada
Chikai
C
Tsuzuki
Minoru
M
Sakurada
Tsukasa
T
D000700:Analgesics / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D002070:Butadienes / Q000494:pharmacology; D000697:Central Nervous System Stimulants / Q000008:administration & dosage / Q000633:toxicity*; D006152:Cyclic GMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007278:Injections, Spinal; D054833:Isoindoles / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009022:Morphine Derivatives / Q000008:administration & dosage / Q000633:toxicity*; D009569:Nitric Oxide / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D009619:Nociceptors / Q000187:drug effects*; D010146:Pain / Q000523:psychology*; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology; D011761:Pyrrolidonecarboxylic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D018039:Receptors, Tachykinin / Q000037:antagonists & inhibitors; D013047:Specific Pathogen-Free Organisms; D013116:Spinal Cord / Q000378:metabolism*; D013237:Stereoisomerism; D013373:Substance P / Q000008:administration & dosage / Q000494:pharmacology
D000700:Analgesics; D002070:Butadienes; D000697:Central Nervous System Stimulants; D004791:Enzyme Inhibitors; D054833:Isoindoles; D009022:Morphine Derivatives; D009570:Nitriles; D010446:Peptide Fragments; D010880:Piperidines; D018039:Receptors, Tachykinin; C113580:U 0126; C071693:7,7-diphenyl-2-(1-imino-2-(2-methoxyphenyl)ethyl)perhydroisoindol-4-one; C080755:3-(2-methoxybenzylamino)-2-phenylpiperidine; D009569:Nitric Oxide; D013373:Substance P; C032292:substance P (6-11); D048049:Extracellular Signal-Regulated MAP Kinases; D006152:Cyclic GMP; C018108:morphine-3-glucuronide; D011761:Pyrrolidonecarboxylic Acid