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.