Changes in Spinal BDNF Activity with Altered PSA-NCAM Expression in a Mouse Model of Inflammatory Pain

Chronic pain affects the quality of life of millions people and costs countries the equivalent of millions of dollars each year. Growing scientific research has linked chronic pain with changes in the central nervous system (synaptic plasticity) at the level of the spinal cord. Central sensitization is the mechanism accounting for these changes and it shares many similarities with long-term potentiation (LTP), the mechanism for memory formation in the hippocampus. Polysialylated neural cell adhesion molecule (PSA-NCAM) is a recognized player in neural development and LTP. In this thesis, we investigated its role in a mouse model of persistent inflammatory pain. Polysialic acid (PSA) modifies the neural cell adhesion molecule (NCAM) mediated cell to cell adhesion and is essential in axonal growth and the induction and maintenance of LTP. We knocked down polysialyltransferases responsible for the attachment of PSA to NCAM using intrathecal injection of small interfering RNAs (siRNAs) and were able to show that decreased levels of PSA-NCAM lead to attenuation of carrageenan-induced hyperalgesia. Previous studies by others have shown that changes in PSA-NCAM levels are also associated with alterations in brain-derived neurotrophic factor (BDNF) signaling in LTP. This finding, coupled with prior research from our lab and others that show that BDNF and its high affinity tyrosine kinase (trkB) receptor are increased in the spinal cord of mice with persistent inflammatory pain, led us to investigate the changes in spinal BDNF signaling in this knock-down study. Results from our immunohistochemical studies show that the knockdown of polysialyltransferases leads to a decrease in the active, phosphorylated form of trkB receptors in the dorsal horn of the spinal cord, suggesting that PSA-NCAM levels affect the activation of trkB receptors in vivo. These findings provide insights into the molecular changes underlying persistent pain and may have implications for novel therapeutic targets in the treatment or prevention of persistent pain