NMDA receptor antagonist treatment at the time of nerve injury prevents injury-induced changes in spinal NR1 and NR2B subunit expression and increases the sensitivity of residual pain behaviours to subsequently administered NMDA receptor antagonists

Abstract

Spinal NMDA receptors (NMDA R) are important in neuropathic sensitisation and acute administration of antagonists can provide temporary attenuation of sensitisation. If establishment of the chronic pain state could be prevented by brief administration of such agents at or around the time of nerve injury (pre-emptive analgesia) it might be possible to avoid many of the unacceptable side effects associated with repeated administration of these or other antagonists. Several reports describe aspects of effective pre-emptive analgesia from NMDA R antagonists in animal models of neuropathic pain. The first aim of the present study was to make a direct comparison of changes in mechanical allodynia, cold allodynia and thermal hyperalgesia following nerve injury, demonstrating their increasing degree of susceptibility to pre-emptive NMDA R antagonist treatment. Secondly, we used immunoblotting and immunohistochemistry to investigate the effects of nerve injury on NMDA receptor subunit expression, revealing increased expression of NR2B, but not NR2A and reduced NR1 in the superficial dorsal horn. These changes were attenuated following NMDA receptor antagonist pre-treatment. Thirdly, we investigated the pharmacological properties of residual mechanical allodynia and cold allodynia that remained after pre-emptive treatment and revealed a greater sensitivity to NMDA R antagonists. These findings indicate that in addition to a marked suppression of thermal hyperalgesia and cold allodynia, pre-emptive treatment with NMDA R antagonist causes a lasting change in spinal NMDA R complexes such that remaining mechanical allodynia should be more effectively targeted by NMDA R antagonists.

Targeting the NMDA Receptor Subunit NR2B for the Treatment of Neuropathic Pain

“…In a rat neuropathic pain model of L5 spinal nerve transection, there was reduced expression of NR2A, 15 whereas in a model of partial chronic constriction injury to the sciatic nerve there was increased expression of NR2B (but not NR2A) and reduced NR1 in the superficial dorsal horn. 63 In animal neuropathic pain models, NMDA receptor channel blockers such as memantine, MK801, and ketamine attenuate thermal and mechanical hyperalgesia in rats. 64 In a mouse model, conditional deletion of the NR1 subunit in spinal cord resulted in reductions in NMDAmediated current and inflammatory pain, 65 but that study did not address neuropathic pain.…”

Effect of Memantine on the Levels of Neuropeptides and Microglial Cells in the Brain Regions of Rats with Neuropathic Pain

“…Several behavioral studies have demonstrated that memantine attenuates allodynia and hyperalgesia postsciatic nerve injury and formalin injection (Carlton and Hargett 1995;Eisenberg et al 1995;Medvedev et al 2004;Wilson et al 2005). Memantine, noncompetitive NMDA receptor antagonist, is being used now to be a clinically promising drug for Alzheimer's disease in Europe and USA, because of its low neurotoxicity (Kato 2004).…”

Blockade of Glycine Transporter (GlyT) 2, but Not GlyT1, Ameliorates Dynamic and Static Mechanical Allodynia in Mice With Herpetic or Postherpetic Pain

“…The present study demonstrated that intrathecal strychnineinduced dynamic allodynia was inhibited by intrathecal sarcosine (and also by ALX1393), supporting the ability of GlyT1 inhibitor to enhance glycinergic inhibition. However, the expression of GlyT1 is very high in the laminae I and II of the dorsal horn (33), an area where the expression of NMDA receptors is rich (41,42). Glycine acts as an essential co-agonist of glutamate at NMDA receptors (30), and its binding to the modulatory site of NMDA receptor is necessary for ion-channel opening (31).…”