Slow modulation of synaptic transmission by brain-derived neurotrophic factor leads to the central sensitization associated with neuropathic pain

Chronic constriction injury (CCI) of the rat sciatic nerve increases the dorsal horn excitability. This “central sensitization” leads to behavioral manifestations analogous to those related to human neuropathic pain. We found, using whole-cell recording from acutely isolated spinal cord slices, that 7-to 10-day-long CCI increases excitatory synaptic drive to putative excitatory “delay”-firing neurons in the substantia gelatinosa but attenuates that to putative inhibitory “tonic”-firing neurons. A defined-medium organotypic culture (DMOTC) system was used to investigate the long-term actions of brain-derived neurotrophic factor (BDNF) as a possible instigator of these changes. When all five neuronal types found in the substantia gelatinosa were considered, BDNF and CCI produced similar patterns, or “footprints,” of changes across the whole population. This pattern was not seen with another putative “pain mediator,” interleukin 1β. Thus, BDNF decreased synaptic drive to “tonic” neurons and increased synaptic drive to “delay” neurons. Actions of BDNF on “delay” neurons were presynaptic and involved increased mEPSC frequency and amplitude without changes in the function of postsynaptic AMPA receptors. By contrast, BDNF exerted both pre-and post-synaptic actions on “ tonic” cells to reduce the mEPSC frequency and amplitude. These differential actions of BDNF on excitatory and inhibitory neurons contributed to a global increase in the dorsal horn network excitability as assessed by the amplitude of depolarization-induced increases in the intracellular Ca²⁺]. Experiments with the BDNF-binding protein TrkB-d5 provided additional evidence for BDNF as a harbinger of neuropathic pain. Thus, the cellular processes altered by BDNF likely contribute to “central sensitization” and hence to the onset of neuropathic pain. Neirofiziologiya/Neurophysiology, Vol. 39, Nos. 4/5, pp. 315–326, July–October, 2007.