NMDA receptors are implicated in central sensitisation underlying
chronic pain, and
NMDA antagonists have a potential for the treatment of
neuropathic pain. Functional
NMDA receptors are also present on primary afferents, where they may play a role in pro-nociceptive plasticity. The importance of this mechanism in
neuropathic pain remains unclear. In the present work, we have compared in models of
chronic pain the effects of
NMDA antagonists at the
glycine(B) site with different central access.
L-701,324 (the centrally active antagonist) and
5,7-dichlorokynurenic acid (5,7-DCK, known to have limited central access) were tested after systemic administration in rats in the
formalin test and in two models of
neuropathic pain. The ability of these compounds to exert central actions (sedation,
ataxia) was tested in the open field locomotion test; central
NMDA antagonism in vivo was tested in anaesthetised rats on responses of spinal cord neurones to iontophoretic
NMDA. Both
L-701,324 (2.15-21.5 mg/kg i.p.) and 5,7-DCK (10-46.4 mg/kg i.v.) dose-dependently inhibited Phase II of
formalin-evoked behaviour. Likewise, both compounds reversed cold
allodynia in the chronic constriction injury model and
tactile allodynia in animals with spinal nerve
ligation. However, only
L-701,324 was able to inhibit neuronal responses to
NMDA in the antihyperalgesic dose range; 5,7-DCK was inactive on
NMDA responses up to 46.4 mg/kg i.v. or 68.1 mg/kg i.p. Consistent with the lack of inhibition of central
NMDA-evoked activity, 5,7-DCK did not alter spontaneous behaviour in the open field test, whereas it was significantly inhibited by
L-701,324. Thus, peripheral
NMDA receptors may substantially contribute to the efficacy of
NMDA antagonists in
neuropathic pain.