Brain-derived neurotrophic factor (BDNF) is up-regulated and released in the dorsal horn following peripheral inflammation and has therefore been implicated in spinal mechanisms of sensitization. Despite these observations, the mechanisms associated with such a role for BDNF are not yet fully determined. Here, we investigate the effect of BDNF on dorsal root-evoked synaptic transmission in lamina II neurons. In a transverse spinal cord slice preparation from neonatal rats (P1-15), the whole cell patch-clamp technique was used to record from these neurons. Brief application of BDNF (50-200 ng/mL) facilitated the evoked synaptic currents; they remained enhanced even after BDNF was washed out. A significant minority of cells was minimally affected by BDNF and consistent with this, not all neurons in lamina II were immunoreactive for the tyrosine kinase (trk) B receptor. No facilitation was elicited when N-methyl-d-aspartate (NMDA) receptors were blocked with D-APV, when the postsynaptic NMDA receptors were selectively blocked with intracellular MK-801, or when postsynaptic neurons were loaded with BAPTA. Additionally, inhibiting phospholipase C (PLC) or protein kinase C (PKC) prior to BDNF application completely blocked facilitation. However, once synaptic current underwent BDNF-induced facilitation, the PKC inhibitors failed to reverse the effect, suggesting that PKC is needed for initiation, but not maintenance of BDNF-induced facilitation. These results demonstrate that BDNF functions at the spinal level to enhance synaptic efficacy in an NMDA receptor-dependent manner and requires the action of the PLC/PKC pathway. This action of BDNF may contribute to central sensitization and exaggerated pain states.

We previously showed that peripheral noxious input after spinal cord injury (SCI) inhibits beneficial spinal plasticity and impairs recovery of locomotor and bladder functions. These observations suggest that noxious input may similarly affect the development and maintenance of chronic neuropathic pain, an important consequence of SCI. In adult rats with a moderate contusion SCI, we investigated the effect of noxious tail stimulation, administered one day after SCI, on mechanical withdrawal responses to von Frey stimuli from 1 to 28 days, post-treatment. In addition, because the pro-inflammatory cytokine tumor necrosis factor α (TNFα) is implicated in numerous injury-induced processes including pain hypersensitivity, we assessed the temporal and spatial expression of TNFα, TNF receptors, and several downstream signaling targets after stimulation. Our results showed that unlike sham surgery or SCI only, nociceptive stimulation following SCI induced mechanical sensitivity by 24 hours. These behavioral changes were accompanied by increased expression of TNFα. Cellular assessments of downstream targets of TNFα revealed that nociceptive stimulation increased the expression of caspase 8 and the active subunit (12 kDa) of caspase 3 at a time point consistent with the onset of mechanical allodynia, indicative of active apoptosis. In addition, immunohistochemical analysis revealed distinct morphological signs of apoptosis in neurons and microglia at 24 hours post-stimulation. Interestingly, expression of the inflammatory mediator NFκB was unaltered by nociceptive stimulation. These results suggest that noxious input caudal to the level of SCI can increase the onset and expression of behavioral responses indicative of pain, potentially involving TNFα signaling.

Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophic factor family of signaling molecules. Since its discovery over three decades ago, BDNF has been identified as an important regulator of neuronal development, synaptic transmission, and cellular and synaptic plasticity and has been shown to function in the formation and maintenance of certain forms of memory. Neural plasticity that underlies learning and memory in the hippocampus shares distinct characteristics with spinal cord nociceptive plasticity. Research examining the role BDNF plays in spinal nociception and pain overwhelmingly suggests that BDNF promotes pronociceptive effects. BDNF induces synaptic facilitation and engages central sensitization-like mechanisms. Also, peripheral injury-induced neuropathic pain is often accompanied with increased spinal expression of BDNF. Research has extended to examine how spinal cord injury (SCI) influences BDNF plasticity and the effects BDNF has on sensory and motor functions after SCI. Functional recovery and adaptive plasticity after SCI are typically associated with upregulation of BDNF. Although neuropathic pain is a common consequence of SCI, the relation between BDNF and pain after SCI remains elusive. This article reviews recent literature and discusses the diverse actions of BDNF. We also highlight similarities and differences in BDNF-induced nociceptive plasticity in naïve and SCI conditions.