Pain Facilitation and Activity-Dependent Plasticity in Pain Modulatory Circuitry: Role of BDNF-TrkB Signaling and NMDA Receptors

Abstract

Pain modulatory circuitry in the brainstem exhibits considerable synaptic plasticity. The increased peripheral neuronal barrage after injury activates spinal projection neurons that then activate multiple chemical mediators including glutamatergic neurons at the brainstem level, leading to an increased synaptic strength and facilitatory output. It is not surprising that a well-established regulator of synaptic plasticity, brain-derived neurotrophic factor (BDNF), contributes to the mechanisms of descending pain facilitation. After tissue injury, BDNF and TrkB signaling in the brainstem circuitry is rapidly activated. Through the intracellular signaling cascade that involves phospholipase C, inositol trisphosphate, protein kinase C, and nonreceptor protein tyrosine kinases; N-methyl-D-aspartate (NMDA) receptors are phosphorylated, descending facilitatory drive is initiated, and behavioral hyperalgesia follows. The synaptic plasticity observed in the pain pathways shares much similarity with more extensively studied forms of synaptic plasticity such as long-term potentiation (LTP) and long-term depression (LTD), which typically express NMDA receptor dependency and regulation by trophic factors. However, LTP and LTD are experimental phenomena whose relationship to functional states of learning and memory has been difficult to prove. Although mechanisms of synaptic plasticity in pain pathways have typically not been related to LTP and LTD, pain pathways have an advantage as a model system for synaptic modifications as there are many well-established models of persistent pain with clear measures of the behavioral phenotype. Further studies will elucidate cellular and molecular mechanisms of pain sensitization and further our understanding of principles of central nervous system plasticity and responsiveness to environmental challenge.

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Acknowledgement

The authors’ work is supported by NIH grants DA10275, DE11964, NS059028.

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Correspondence to Ke Ren.

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Ren, K., Dubner, R. Pain Facilitation and Activity-Dependent Plasticity in Pain Modulatory Circuitry: Role of BDNF-TrkB Signaling and NMDA Receptors. Mol Neurobiol 35, 224–235 (2007). https://doi.org/10.1007/s12035-007-0028-8

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Keywords

  • Hyperalgesia
  • Tissue injury
  • Neurotrophins
  • Brainstem
  • Phosphorylation
  • Inflammation
  • Periaqueductal gray
  • Rostral ventromedial medulla
  • Signal transduction