title: Antinociceptive effects of N-acetylaspartylglutamate (NAAG) peptidase inhibitors ZJ-11, ZJ-17 and ZJ-43 in the rat formalin test and in the rat neuropathic pain model.
abstract: The peptide neurotransmitter N-acetylaspartylglutamate (NAAG) acts as an agonist at group II metabotropic glutamate receptors (mGluRs). NAAG is inactivated by extracellular peptidase activity yielding glutamate and N-acetylaspartate. We recently developed a series of potent NAAG peptidase inhibitors, including ZJ-11, ZJ-17 and ZJ-43. In the present study, we examined the effects of intrathecally administered ZJ-11 and ZJ-17 and intravenously administered ZJ-11 and ZJ-43 in the rat formalin test (an inflammatory pain model) and in the rat partial sciatic nerve ligation model (a neuropathic pain model). Intrathecal injection of ZJ-11 or ZJ-17 or intravenous injection of ZJ-11 or ZJ-43 suppressed both phases of the agitation behaviour induced by paw formalin injection. Intrathecal and intravenous injection of ZJ-11 suppressed the expression of Fos-like immunoreactivity, induced by paw formalin injection, in laminae I-II in segments L4-L5 of the spinal cord, suggesting an action on sensory spinal transmission. Partial sciatic nerve ligation induced significant mechanical allodynia 7 days after the nerve injury. Intrathecal injection of ZJ-11 or ZJ-17 or intravenous administration of ZJ-11 or ZJ-43 attenuated the level of mechanical allodynia induced by this nerve ligation. These effects of intrathecally or intravenously administered ZJ compounds in both the formalin test and the partial sciatic nerve ligation model were completely antagonized by pretreatment with LY-341495, a highly selective group II mGluR antagonist. Thus, elevation of extracellular NAAG, induced by the inhibition of NAAG peptidase, activates group II mGluRs and produces an analgesic effect in neuropathic and inflammatory and pain models. In contrast, peptidase inhibition did not affect the threshold for withdrawal from a noxious mechanical stimulus or from an acute thermal stimulus in the hotplate test.
authors.affiliation: Department of Anaesthesiology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba-shi, Chiba 260-8670, Japan. yamamotot@faculty.chiba-u.jp
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Serabi
authors.initials: S
authors.lastname: Hirasawa
authors.forename: Barbara
authors.initials: B
authors.lastname: Wroblewska
authors.forename: Ewa
authors.initials: E
authors.lastname: Grajkowska
authors.forename: Jia
authors.initials: J
authors.lastname: Zhou
authors.forename: Alan
authors.initials: A
authors.lastname: Kozikowski
authors.forename: Jarda
authors.initials: J
authors.lastname: Wroblewski
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Neale
mesh_terms: D000596:Amino Acids / Q000494:pharmacology; D000700:Analgesics / Q000627:therapeutic use*; D000818:Animals; D001522:Behavior, Animal; D002460:Cell Line; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D043425:Glutamate Carboxypeptidase II / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D007275:Injections, Intravenous / Q000379:methods; D007278:Injections, Spinal / Q000379:methods; D009619:Nociceptors / Q000187:drug effects; D010146:Pain / Q000188:drug therapy*; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D017288:Pain Threshold / Q000187:drug effects; D010812:Physical Stimulation; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D011930:Reaction Time / Q000187:drug effects; D020426:Sciatic Neuropathy / Q000188:drug therapy; D014508:Urea / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000737:chemistry / Q000627:therapeutic use*; D014966:Xanthenes / Q000494:pharmacology
chemical_list: D000596:Amino Acids; D000700:Analgesics; D018691:Excitatory Amino Acid Antagonists; C114624:LY 341495; D011480:Protease Inhibitors; D016760:Proto-Oncogene Proteins c-fos; D014966:Xanthenes; C491011:ZJ-11 compound; C491010:ZJ-17 compound; C486211:ZJ43; D014508:Urea; D043425:Glutamate Carboxypeptidase II