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Mechanisms underlying spontaneous functional sensory changes following spinal deafferentation Soril, Lesley Jeanne Josephine


Dorsal root injury (DRI) induces both pain and anatomical changes in pain-processing systems in the deafferented dorsal horn. Brain-derived neurotrophic factor (BDNF) is also upregulated in the spinal cord following DRI and is thought to participate in nociceptive transmission and stimulation of axon outgrowth. Transection of the C7 and C8 dorsal roots (C7/8 DRI) generates cold pain in the ipsilateral forepaw which peaks at 10 days, and resolves within three weeks after injury. In this thesis I sought to investigate the influence of BDNF on cold pain behaviour following C7/8 DRI. Increased BDNF expression by Ox-42-positive microglia was observed up to 20 days post-C7/8 DRI. To determine the acute facilitatory effects of this increased BDNF on cold pain behaviour, intrathecal boli of TrkB-Fc ‘receptor bodies’ were administered following DRI and resulted in reduced peak response duration to peripheral cooling stimuli. However, long-term BDNF sequestration with continuous TrkB-Fc infusion failed to reduce cold pain and prevented the spontaneous recovery normally seen after three weeks. Prolonged BDNF sequestration also prevented the increase in serotonergic and GABAergic terminal densities which normally follows C7/8 DRI, and simultaneously stimulated sprouting of nociceptive primary afferents. These results dually implicate endogenous BDNF in modulating synaptic transmission and governing the plasticity of inhibitory circuitry in the deafferented spinal cord to, indirectly, promote the recovery from cold pain that develops following C7/8 DRI. We also investigated the effects of exogenous BDNF treatment in DRI-induced cold pain and hypothesized that at high concentrations, BDNF would have a preventative effect. Surprisingly, exogenous BDNF treatment also impeded cold pain recovery, which was not attributable to sprouting of nociceptive terminals. Exogenous BDNF did, however, increase the density of the inhibitory adrenergic/noradrenergic, dopaminergic and GABAergic terminals, whereas DRI-induced serotonergic sprouting was unaffected. BDNF also down-regulated spinal K⁺/Cl- co-transporter-2 (KCC2) expression, possibly resulting in conversion of GABAergic signaling (itself probably amplified subsequent to sprouting) from inhibitory to excitatory. These results illustrate the differential and exquisite levels of control which BDNF exerts over distinct populations of spinally-projecting axons, and the effects of exogenous BDNF on DRI-induced axonal plasticity and cold pain.

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