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

Tatsuo Yamamoto, Serabi Hirasawa, Barbara Wroblewska, Ewa Grajkowska, Jia Zhou, Alan Kozikowski, Jarda Wroblewski, Joseph H. Neale

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)483-494
Number of pages12
JournalEuropean Journal of Neuroscience
Volume20
Issue number2
DOIs
StatePublished - Jul 2004
Externally publishedYes

Fingerprint

Glutamate Carboxypeptidase II
Neuralgia
Pain Measurement
Protease Inhibitors
Spinal Injections
Ligation
Sciatic Nerve
Metabotropic Glutamate Receptors
Hyperalgesia
Intravenous Injections
Formaldehyde
LY 341495
Peptide Hydrolases
Injections
Intravenous Administration
Neurotransmitter Agents
Analgesics
Glutamic Acid
Spinal Cord
Hot Temperature

Keywords

  • Fos
  • Group II metabotropic glutamate receptors
  • Inflammatory pain
  • LY-341495
  • Mechanical allodynia
  • NAAG
  • NAAG peptidase
  • Neuropathic pain

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

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. / Yamamoto, Tatsuo; Hirasawa, Serabi; Wroblewska, Barbara; Grajkowska, Ewa; Zhou, Jia; Kozikowski, Alan; Wroblewski, Jarda; Neale, Joseph H.

In: European Journal of Neuroscience, Vol. 20, No. 2, 07.2004, p. 483-494.

Research output: Contribution to journalArticle

Yamamoto, Tatsuo ; Hirasawa, Serabi ; Wroblewska, Barbara ; Grajkowska, Ewa ; Zhou, Jia ; Kozikowski, Alan ; Wroblewski, Jarda ; Neale, Joseph H. / 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. In: European Journal of Neuroscience. 2004 ; Vol. 20, No. 2. pp. 483-494.
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