title: Intrathecal high-dose morphine induces spinally-mediated behavioral responses through NMDA receptors.
abstract: Previous research has demonstrated that intrathecal i.t. morphine in a dose of 60.0 nmol into the spinal subarachnoid space of mice can evoke nociceptive behavioral responses consisting of a severe hindlimb scratching directed toward the flank followed by biting/licking of the hindpaw. The present study was undertaken to examine the involvement of spinal N-methyl-D-aspartate (NMDA) and opioid receptors on the behavioral responses evoked by high-dose i.t. morphine. Pretreatment with naloxone, an opioid receptor antagonist (1.0 and 4.0 mg/kg, s.c.), failed to reverse the morphine-evoked behavioral response, suggesting that the morphine effect is not mediated through the opioid receptors in the spinal cord. The morphine-induced behavior was dose-dependently inhibited by i.t. co-administration of the competitive NMDA receptor antagonists, D(-)-2-amino-5-phosphonovaleric acid (D-APV) (6.25-50.0 pmol) and 3-((+)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP) (3.125-25.0 pmol). The characteristic behavior was also reduced by co-administration of (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5,10-imine maleate (MK-801) (74.1-250 pmol), an NMDA ion-channel blocker. Ifenprodil, a competitive antagonist of the polyamine recognition site of NMDA receptor ion channel complex, produced a dose-related inhibitory effect on the behavioral response to i.t. morphine with less potency than the competitive and non-competitive antagonists examined. High doses of (+)-HA-966, a glycine/NMDA antagonist, induced a dose-dependent inhibition of morphine-induced response. The effective dose of i.t. 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), a non-NMDA receptor antagonist, needed to reduce the morphine-induced response, was approximately 10-fold greater than that of D-APV. These results suggest that spinal NMDA receptors, but not non-NMDA receptors, may be largely involved in elicitation of the behavioral episode following i.t. injection of morphine in mice.
authors.affiliation: Department of Biochemistry, Daiichi College of Pharmaceutical Sciences, 22-1 Tamagawa-cho, Minami-ku, 815-8511, Fukuoka, Japan. tsukasa@daiichi-cps.ac.jp
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Sakurada
authors.forename: Chizuko
authors.initials: C
authors.lastname: Watanabe
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Okuda
authors.forename: Akinori
authors.initials: A
authors.lastname: Sugiyama
authors.forename: Tomoko
authors.initials: T
authors.lastname: Moriyama
authors.forename: Chikai
authors.initials: C
authors.lastname: Sakurada
authors.forename: Koichi
authors.initials: K
authors.lastname: Tan-No
authors.forename: Shinobu
authors.initials: S
authors.lastname: Sakurada
mesh_terms: D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000502:physiology*; D006614:Hindlimb / Q000294:innervation; D006930:Hyperalgesia / Q000139:chemically induced* / Q000503:physiopathology; D007278:Injections, Spinal; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009020:Morphine / Q000008:administration & dosage / Q000633:toxicity*; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000187:drug effects / Q000502:physiology; D010147:Pain Measurement; D010879:Piperazines / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D011930:Reaction Time / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects* / Q000502:physiology; D011957:Receptors, Opioid / Q000187:drug effects / Q000502:physiology; D013116:Spinal Cord / Q000503:physiopathology; D013346:Subarachnoid Space
chemical_list: D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D009292:Narcotic Antagonists; D009419:Nerve Tissue Proteins; D010879:Piperazines; D010880:Piperidines; D011760:Pyrrolidinones; D016194:Receptors, N-Methyl-D-Aspartate; D011957:Receptors, Opioid; D009270:Naloxone; D018698:Glutamic Acid; D016291:Dizocilpine Maleate; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D015763:2-Amino-5-phosphonovalerate; D009020:Morphine; C050592:3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid; C001369:1-hydroxy-3-amino-2-pyrrolidone; C010739:ifenprodil