Contribution of the spinal cord BDNF to the development of neuropathic pain by activation of the NR2B-containing NMDA receptors in rats with spinal nerve ligation

The NMDA receptor and the brain-derived neurotrophic factor (BDNF) are involved in central sensitization and synaptic plasticity in the spinal cord To determine whether the spinal cord BDNF contributes to the development and maintenance Of neuropathic pain by activation of the dorsal horn NR2B-contaming NMDA (NMDA-2B) receptors, this study was designed to investigate if alterations in BDNF and its Trk13 receptor in the spinal dorsal horn Would parallel the tirneline of the development of neuropathic pain in lumbar 5 (L5) spinal nerve ligated (SNL) rats The enzyme-linked immunosorbent assay (ELISA) showed that the BDNF concentration significantly increased during 24 It post-surgery, and the maximal enhancement lasted for 48 h It declined as time progressed and returned to the level of pre-operation at 28 days after SNL. In parallel with the alteration of BDNF concentration in the spinal dorsal horn, the 50% paw withdrawal threshold (PWT) of the ipsilateral hind paw in SNL rats also showed a significant decrease during 24-48 h after SNL as compared with those in sham-operated rats The correlation analysis revealed that the BDNF concentration had a negative correlation with 50% PWT in early stage (0-48 h) (r = -0 974, p = 0 001), but [lot late stage (3-28 days) (r = 0 3395, p = 0 6605), after SNL. Similarly, the immunohistochemical staining revealed that a significant up-regulation of BDNF expression in the spinal dorsal horn appeared as early as 12 h post-operation in SNL in rats, peaked at 24-48 h, declined at 3 days and disappeared at 14 days after SNL In contrast, an increase in NMDA-2B receptors expression in the spinal dorsal horn was delayed to 48 h after SNL The increase reached peak at 3 days. lasted for 14 days, and returned to the control level of pre-operation at 28 days after SNL The maximal enhancement of BDNF expression Occurred in early stage (24-48 h) after nerve injury. while the peak of NMDA-2B receptors expression appeared in late stage (3-14 days) post-nerve ligation. As compared with the dynamic changes of 50% PWT in the timeline after nerve injury, the maximal enhancement of BDNF expression closely paralleled the maximal decline in the slope of 50% PWT. while the peak of NMDA-2B receptors expression corresponded with the plateau of the decreased 50% PWT. Therefore. the increased BDNF in the spinal dorsal horn was likely to be associated with the initiation of neuropathic pain in early stage (0-48 h), while the activation of NMDA-213 receptors was involved in the maintenance of persistent pain states in late stage (2-14 days) after nerve injury Moreover, the present study also demonstrated that the BDNF/TrkB-mediated signaling pathway within the spinal cord might be involved in the induction of neuropathic pain in early stage after nerve injury, and the selective NMDA-213 receptors antagonist (Ro 25-6981) almost completely blocked the BDNF-mduced mechanical allodynia in all of the tested rats These data suggested that the BDNF/TrkB-mediated signaling pathway in the spinal cord was involved in the development of nerve injury-induced neuropathic pain through the activation of dorsal horn NMDA-213 receptors (D 2010 Elsevier Inc All rights reserved.