title: Intrathecally administered big dynorphin, a prodynorphin-derived peptide, produces nociceptive behavior through an N-methyl-D-aspartate receptor mechanism.
abstract: Intrathecal (i.t.) administration of big dynorphin (1-10 fmol), a prodynorphin-derived peptide consisting of dynorphin A and dynorphin B, to mice produced a characteristic behavioral response, the biting and/or licking of the hindpaw and the tail along with slight hindlimb scratching directed toward the flank, which peaked at 5-15 min after an injection. Dynorphin A produced a similar response, though the doses required were higher (0.1-30 pmol) whereas dynorphin B was practically inactive even at 1000 pmol. The behavior induced by big dynorphin (3 fmol) was dose-dependently inhibited by intraperitoneal injection of morphine (0.125-2 mg/kg) and also dose-dependently, by i.t. co-administration of D(-)-2-amino-5-phosphonovaleric acid (D-APV) (1-4 nmol), a competitive N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801 (0.25-4 nmol), an NMDA ion-channel blocker, and ifenprodil (2-8 pmol), an inhibitor of the NMDA receptor ion-channel complex interacting with the NR2B subunit and the polyamine recognition site. On the other hand, naloxone, an opioid receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), a non-NMDA glutamate receptor antagonist, 7-chlorokynurenic acid, a competitive antagonist of the glycine recognition site on the NMDA receptor ion-channel complex, [D-Phe(7),D-His(9)]-substance P(6-11), a specific antagonist for substance P (NK1) receptors, and MEN-10376, a tachykinin NK2 receptor antagonist, had no effect. These results suggest that big dynorphin-induced nociceptive behavior is mediated through the activation of the NMDA receptor ion-channel complex by acting on the NR2B subunit and/or the polyamine recognition site but not on the glycine recognition site, and does not involve opioid, non-NMDA glutamate receptor mechanisms or tachykinin receptors in the mouse spinal cord.
mesh_terms: D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004399:Dynorphins / Q000494:pharmacology*; D004723:Endorphins / Q000494:pharmacology; D004745:Enkephalins / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D007278:Injections, Spinal; D007736:Kynurenic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D051379:Mice; D009020:Morphine / Q000494:pharmacology; D015288:Neurokinin A / Q000031:analogs & derivatives* / Q000494:pharmacology; D009619:Nociceptors / Q000187:drug effects* / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011498:Protein Precursors / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D018039:Receptors, Tachykinin / Q000037:antagonists & inhibitors; D013373:Substance P / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D000701:Analgesics, Opioid; D004723:Endorphins; D004745:Enkephalins; D018691:Excitatory Amino Acid Antagonists; D010446:Peptide Fragments; D010880:Piperidines; D011498:Protein Precursors; D016194:Receptors, N-Methyl-D-Aspartate; D018039:Receptors, Tachykinin; C069192:neurokinin A(4-10), Tyr(5)-Trp(6,8,9)-Lys(10)-; D013373:Substance P; D016291:Dizocilpine Maleate; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D004399:Dynorphins; D015763:2-Amino-5-phosphonovalerate; D009020:Morphine; C036200:rimorphin; D015288:Neurokinin A; C033660:preproenkephalin; D007736:Kynurenic Acid; C010739:ifenprodil; C057013:7-chlorokynurenic acid