Pronociceptive role of dynorphins in uninjured animals: N-ethylmaleimide-induced nociceptive behavior mediated through inhibition of dynorphin degradation.
Intrathecal (i.t.) administration into mice of N-ethylmaleimide (NEM), a cysteine protease inhibitor, 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. The behavior induced by NEM was inhibited by the intraperitoneal injection of morphine. We have recently reported that dynorphin A and, more potently big dynorphin, consisting of dynorphins A and B, produce the same type of nociceptive response whereas dynorphin B does not [Tan-No K, Esashi A, Nakagawasai O, Niijima F, Tadano T, Sakurada C, Sakurada T, Bakalkin G, Terenius L, Kisara K. Intrathecally administered big dynorphin, a prodynorphin-derived peptide, produces nociceptive behavior through an N-methyl-d-aspartate receptor mechanism. Brain Res 2002;952:7-14]. The NEM-induced nociceptive behavior was inhibited by pretreatment with dynorphin A- or dynorphin B-antiserum and each antiserum also reduced the nociceptive effects of i.t.-injected synthetic big dynorphin. The characteristic NEM-evoked response was not observed in prodynorphin knockout mice. Naloxone, an opioid receptor antagonist, had no effects on the NEM-induced behavior. Ifenprodil, arcaine and agmatine, antagonists at the polyamine recognition site on the N-methyl-D-aspartate (NMDA) receptor ion-channel complex, and MK-801, an NMDA ion-channel blocker inhibited the NEM-induced effects. Ro25-6981, an antagonist of the NMDA receptor subtype containing NR2B subunit was not active. NEM completely inhibited degradation of dynorphin A by soluble and particulate fractions of mouse spinal cord. Collectively, the results demonstrate that endogenous prodynorphin-derived peptides are pronociceptive in uninjured animals, and required for the NEM-induced behavior. The NEM effects may be mediated through inhibition of the degradation of endogenous dynorphins, presumably big dynorphin that in turn activates the NMDA receptor ion-channel complex by acting on the polyamine recognition site.
Tan-No
Koichi
K
Department of Pharmacology, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan Department of Pharmacology, Nihon Pharmaceutical University, 10281 Komuro, Ina-cho, Kitaadachi-gun, Saitama 362-0806, Japan Department of Physiology and Anatomy, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan Experimental Alcohol and Drug Addiction Research Section, Department of Clinical Neuroscience, Karolinska Institute, Stockholm S-171 76, Sweden.
Takahashi
Hiroaki
H
Nakagawasai
Osamu
O
Niijima
Fukie
F
Sato
Takumi
T
Satoh
Susumu
S
Sakurada
Shinobu
S
Marinova
Zoya
Z
Yakovleva
Tatjana
T
Bakalkin
Georgy
G
Terenius
Lars
L
Tadano
Takeshi
T
D000376:Agmatine / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001645:Biguanides / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004399:Dynorphins / Q000276:immunology / Q000378:metabolism*; D004745:Enkephalins / Q000235:genetics; D004791:Enzyme Inhibitors / Q000633:toxicity*; D005033:Ethylmaleimide / Q000633:toxicity*; D018691:Excitatory Amino Acid Antagonists; D007106:Immune Sera / Q000494:pharmacology; D007278:Injections, Spinal / Q000379:methods; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009020:Morphine / Q000494:pharmacology; D009294:Narcotics / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011498:Protein Precursors / Q000235:genetics; D011957:Receptors, Opioid / Q000187:drug effects* / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D000094942:Nociceptin Receptor
D001645:Biguanides; D004745:Enkephalins; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D007106:Immune Sera; D009294:Narcotics; D010880:Piperidines; D011498:Protein Precursors; D011957:Receptors, Opioid; C006624:arcaine; D016291:Dizocilpine Maleate; D000376:Agmatine; D004399:Dynorphins; D009020:Morphine; C033660:preproenkephalin; D005033:Ethylmaleimide; C010739:ifenprodil; D000094942:Nociceptin Receptor; C000722287:Oprl1 protein, mouse