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The Journal of Neuroscience, January 4, 2006, 26(1):126-137; doi:10.1523/JNEUROSCI.3686-05.2006

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Behavioral/Systems/Cognitive
Supraspinal Brain-Derived Neurotrophic Factor Signaling: A Novel Mechanism for Descending Pain Facilitation

Wei Guo, ^* Meredith T. Robbins, ^* Feng Wei, ^* Shiping Zou, Ronald Dubner, and Ke Ren

Department of Biomedical Sciences, Program in Neuroscience, Dental School, University of Maryland, Baltimore, Maryland 21201

In the adult mammalian brain, brain-derived neurotrophic factor (BDNF) is critically involved in long-term synaptic plasticity. Here, we show that supraspinal BDNF-tyrosine kinase receptor B (TrkB) signaling contributes to pain facilitation. We show that BDNF-containing neurons in the periaqueductal gray (PAG), the central structure for pain modulation, project to and release BDNF in the rostral ventromedial medulla (RVM), a relay between the PAG and spinal cord. BDNF in PAG and TrkB phosphorylation in RVM neurons are upregulated after inflammation. Intra-RVM sequestration of BDNF and knockdown of TrkB by RNA interference attenuate inflammatory pain. Microinjection of BDNF (10–100 fmol) into the RVM facilitates nociception, which is dependent on NMDA receptors (NMDARs). In vitro studies with RVM slices show that BDNF induces tyrosine phosphorylation of the NMDAR NR2A subunit in RVM via a signal transduction cascade involving IP₃, PKC, and Src. The supraspinal BDNF-TrkB signaling represents a previously unknown mechanism underlying the development of persistent pain. Our findings also caution that application of BDNF for recovery from CNS disorders could lead to undesirable central pain.

Key words: neurotrophin; TrkB; neuronal plasticity; periaqueductal gray; medulla; pain

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Received Aug 31, 2005; revised November 6, 2005; accepted November 6, 2005.

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