The role of spinal nitric oxide and glutamate in nociceptive behaviour evoked by high-dose intrathecal morphine in rats.
Injection of high-dose of morphine into the spinal lumbar intrathecal (i.t.) space of rats elicits a nociceptive behavioural syndrome characterized by periodic bouts of spontaneous agitation and severe vocalization. The induced behavioural response such as vocalization and agitation was observed dose-dependently by i.t. administration of morphine (125-500 nmol). Pretreatment with naloxone (s.c. and i.t.), an opioid receptor antagonist, failed to reverse the morphine-induced behavioural response. The excitatory effect of morphine was inhibited dose-dependently by pretreatment with 3-((+)2-carboxy-piperazin-4-yl)-propyl-1-phosphonic acid (CPP), a competitive N-methyl-D-aspartate (NMDA) receptor antagonist and MK-801, a non-competitive NMDA receptor antagonist. The non-selective nitric oxide (NO) synthase inhibitor N(G)-nitro L-arginine methyl ester (L-NAME) inhibited dose-dependently the behavioural response to high-dose i.t. morphine (500 nmol), whereas D-NAME was without affecting the response to high-dose i.t. morphine. In the present study, we measured NO metabolites (nitrite/nitrate) in the extracellular fluid of rat dorsal spinal cord using in vivo microdialysis. The i.t. injection of morphine (500 nmol) evoked significant increases in NO metabolites and glutamate from the spinal cord. Not only NO metabolites but also glutamate released by high-dose morphine were reduced significantly by pretreatment with L-NAME (400 nmol). Pretreatment with CPP and MK-801 showed a significant reduction of the NO metabolites and glutamate levels elevated by high-dose i.t. morphine. These results suggest that the excitatory action of high-dose i.t. morphine may be mediated by an NMDA-NO cascade in the spinal cord.
Watanabe
Chizuko
C
Center for Laboratory Animal Science, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan Department of Biochemistry, Daiichi College of Pharmaceutical Sciences, 22-1 Tamagawa-cho, Minami-ku, Fukuoka 815-8511, Japan Department of Internal Medicine, Mogi Hospital, 6-1-20 Meinohama, Nishi-ku, Fukuoka 819-0002, Japan Department of Physiology and Anatomy, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan.
Sakurada
Tsukasa
T
Okuda
Kazuhiro
K
Sakurada
Chikai
C
Ando
Ryuichiro
R
Sakurada
Shinobu
S
D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000502:physiology*; D007278:Injections, Spinal; D008297:Male; D009020:Morphine / Q000008:administration & dosage*; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000502:physiology; D010147:Pain Measurement / Q000379:methods*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000502:physiology; D013116:Spinal Cord / Q000187:drug effects / Q000502:physiology*; D014828:Vocalization, Animal / Q000187:drug effects / Q000502:physiology
D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D009569:Nitric Oxide; D018698:Glutamic Acid; D009020:Morphine; D019001:Nitric Oxide Synthase