title: Brain-derived neurotrophic factor drives the changes in excitatory synaptic transmission in the rat superficial dorsal horn that follow sciatic nerve injury.
abstract: Peripheral nerve injury can promote neuropathic pain. The basis of the 'central sensitization' that underlies this often intractable condition was investigated using 14-20-day chronic constriction injury (CCI) of the sciatic nerve of 20-day-old rats followed by electrophysiological analysis of acutely isolated spinal cord slices. In addition, defined-medium organotypic spinal cord slice cultures were exposed for 5-6 days to brain-derived neurotrophic factor (BDNF, 200 ng ml(-1)) or to medium conditioned with activated microglia (aMCM). Since microglial activation is an early consequence of CCI, the latter manipulation allowed us to model the effect of peripheral nerve injury on the dorsal horn in vitro. Using whole-cell recording from superficial dorsal horn neurons, we found that both BDNF and CCI increased excitatory synaptic drive to putative excitatory 'radial delay' neurons and decreased synaptic excitation of inhibitory 'tonic islet/central' neurons. BDNF also attenuated synaptic excitation of putative GABAergic neurons identified by glutamic acid decarboxylase (GAD) immunoreactivity. Intrinsic neuronal properties (rheobase, input resistance and action potential discharge rates) were unaffected. Exposure of organotypic cultures to either BDNF or aMCM increased overall excitability of the dorsal horn, as seen by increased cytoplasmic Ca(2+) responses to 35 mm K(+) as monitored by confocal Fluo-4AM imaging. The effect of aMCM was attenuated by the recombinant BDNF binding protein TrkBd5 and the effect of BDNF persisted when GABAergic inhibition was blocked with SR95531. These findings suggest that CCI enhances excitatory synaptic drive to excitatory neurons but decreases that to inhibitory neurons. Both effects are mediated by nerve injury-induced release of BDNF from microglia.
authors.affiliation: Department of Pharmacology, University of Alberta, Edmonton, Alberta, T6G 2H7, Canada.
authors.forename: Van B
authors.initials: VB
authors.lastname: Lu
authors.forename: James E
authors.initials: JE
authors.lastname: Biggs
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Stebbing
authors.forename: Sridhar
authors.initials: S
authors.lastname: Balasubramanyan
authors.forename: Kathryn G
authors.initials: KG
authors.lastname: Todd
authors.forename: Aaron Y
authors.initials: AY
authors.lastname: Lai
authors.forename: William F
authors.initials: WF
authors.lastname: Colmers
authors.forename: David
authors.initials: D
authors.lastname: Dawbarn
authors.forename: Klaus
authors.initials: K
authors.lastname: Ballanyi
authors.forename: Peter A
authors.initials: PA
authors.lastname: Smith
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology*; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology*; D008297:Male; D009924:Organ Culture Techniques; D020671:Posterior Horn Cells / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020426:Sciatic Neuropathy / Q000503:physiopathology*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D013997:Time Factors
chemical_list: D019208:Brain-Derived Neurotrophic Factor