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
- 28 June 2004
- journal article
- research article
- Published by Wiley in European Journal of Neuroscience
- Vol. 20 (2), 483-494
- https://doi.org/10.1111/j.1460-9568.2004.03504.x
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.Keywords
This publication has 59 references indexed in Scilit:
- NAAG fails to antagonize synaptic and extrasynaptic NMDA receptors in cerebellar granule neuronsNeuropharmacology, 2004
- GCP II (NAALADase) Inhibition Suppresses Mossy Fiber-CA3 Synaptic Neurotransmission by a Presynaptic MechanismJournal of Neurophysiology, 2004
- LY341495 is a nanomolar potent and selective antagonist of group II metabotropic glutamate receptorsNeuropharmacology, 1998
- Molecular Cloning of a Peptidase Against N‐Acetylaspartylglutamate from a Rat Hippocampal cDNA LibraryJournal of Neurochemistry, 1997
- The Regional Distribution of N‐Acetylaspartylglutamate (NAAG) and Peptidase Activity Against NAAG in the Rat Nervous SystemJournal of Neurochemistry, 1994
- Comparison of the Antinociceptive Effects of Pre- and Posttreatment with Intrathecal Morphine and MK801, an NMDA Antagonist, on the Formalin Test in the RatAnesthesiology, 1992
- Immunocytochemical localization of the N‐acetyl‐aspartyl‐glutamate (NAAG) hydrolyzing enzyme N‐acetylated α‐linked acidic dipeptidase (NAALADase)Journal of Comparative Neurology, 1992
- Competitive Inhibition of N‐Acetylated‐α‐Linked Acidic Dipeptidase Activity by N‐Acetyl‐L‐Aspartyl‐β‐Linked L‐GlutamateJournal of Neurochemistry, 1990
- Immunohistochemistry and Biosynthesis of N‐Acetylaspartylglutamate in Spinal Sensory GangliaJournal of Neurochemistry, 1987
- Efficient Analysis of Experimental ObservationsAnnual Review of Pharmacology and Toxicology, 1980