Effect of NMDA NR2B antagonist on neuropathic pain in two spinal cord injury models

Abstract

N-Methyl-d-aspartate (NMDA) receptors are thought to play an important role in the processes of central sensitization and pathogenesis of neuropathic pain, particularly after spinal cord injury (SCI). NMDA antagonists effectively reduce neuropathic pain, but serious side effects prevent their use as therapeutic drugs. NMDA NR2B antagonists have been reported to effectively reduce inflammatory and neuropathic pain. In this study, we investigated the effects of NR2B antagonists on neuropathic pain and the expression of NR2B in the spinal cord in 2 SCI models. SCI was induced at T12 by a New York University impactor (contusion) or by sectioning of the lateral half of the spinal cord (hemisection). Ifenprodil (100, 200, 500, 1000nmol) and Ro25-6981 (20, 50, 100, 200nmol) were intrathecally injected and behavioral tests were conducted. Ifenprodil increased the paw withdrawal threshold in both models but also produced mild motor depression at higher doses. Ro25-6981 increased the mechanical nociceptive threshold in a dose-dependent manner without motor depression. NR2B expression was significantly increased on both sides at the spinal segments of L1-2 and L4-5 in the hemisection model but did not change in the contusion model. Increased expression of NR2B in the hemisection model was reduced by intrathecal ifenprodil. These results suggest that intrathecal NMDA NR2B antagonist increased the mechanical nociceptive threshold after SCI without motor depression. A selective subtype of NMDA receptor, such as NR2B, may be a more selective target for pain control because NMDA receptors play a crucial role in the development and maintenance of chronic pain.

N-methyl-D-aspartate receptor antagonist MK-801 prevents apoptosis in rats that have undergone fetal spinal cord transplantation following spinal hemisection

“…By contrast, tissues obtained from mice treated with MK-801 demonstrated no apoptotic cells or fragments. This confirmed the well documented neuroprotective effects of MK-801 and lends support to the potential importance of NMDA antagonists as therapeutic agents in the treatment of acute SCI (11,12). …”

“…Dizocilpine maleate (MK801) is a potent non-competitive NMDA receptor antagonist that blocks the excitotoxic sequelae of ischemia in tissue cultures and animal models of cerebral ischemia, reduces infarct size and improves neurological outcome (5). The efficacies of several NMDA antagonist drugs have been studied in various models of SCI, conducive SCI or in ischemic lesions of the rat spinal cord (11,12,16–19); however, to the best of our knowledge, studies using MK801 to prevent apoptosis in rats that have undergone fetal spinal cord (FSC) transplantation following spinal hemisection have not been reported. Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) reaction and immunohistochemical analysis of B-cell lymphoma-2 (Bcl-2) were used to investigate the effect of the NMDA receptor antagonist MK-801 on apoptosis in rats that have undergone FSC transplantation to treat spinal hemisection.…”

Current and Future Issues in the development of spinal agents for the management of pain

“…One such subtype is the NR2B subunit. Specific antagonists such as Ifenprodil [202], Ro 25-6981 [202,203] and Conantokin G [204] has antihyperpathic effects in models of spinal injury and facilitated processing. Other NMDA ionophore-associated targets for which ligands have been shown to produce analgesia include the glycine binding site and the polyamine binding site [201,205]; iii) Magnesium sulphate is a noncompetitive antagonist of the Nmethyl-d-aspartate (NMDA) receptor and thus can modify nociceptive modulation [206][207].…”

Effect of Shikonin on Spinal Cord Injury in Rats Via Regulation of HMGB1/TLR4/NF-kB Signaling Pathway

“…Excessive inflammation response set barrier to the nerve repair and regeneration [6]. Although current treatments of SCI including drugs, surgery and hyperbaric oxygen intervention partial effectively alleviate SCI injury, side effects and secondary injury still disturb the SCI patient [7,8]. Therefore, a new route and effective manner of cure SCI injury especially secondary injury need to be further explored.…”