A long-term goal of my research is to characterize mechanisms of neuroplasticity associated with tissue injury and chronic pain. My previous studies have demonstrated that the sensitization of nociceptive neurons in trigeminal subnucleus caudalis (Vc), which underlies allodynia and hyperalgesia in the orofacial region, results from the up-regulation of the N-methyl-D-aspartate (NMDA) type glutamate receptor. Recently, we have shown that NMDA receptor activity is regulated by a receptor-associated protein tyrosine kinase-phosphatase complex, which consists of Src family protein tyrosine kinases (PTKs), the Src family PTK activator (protein tyrosine phosphatase alpha (PTPalpha)) and inhibitor (C-terminal Src kinase (Csk)). In this complex, Src family PTKs are principal effectors regulating NMDA channel activity. PTPalpha acts as an endogenous driver for the initiation and maintenance of Src family PTK activity necessary for the constitutive regulation of NMDA receptors while Csk inactivates Src family PTKs and thereby down-regulates NMDA receptors. To date, PTPalpha remains the only phosphatase found to be actively involved in the induction of long-term potentiation (LTP) of excitatory synaptic functions in the central nervous system. Based on these findings I hypothesize that the NMDA receptor-associated PTPalpha-Src-Csk protein complex may play very important roles in the regulation of transducing noxious stimuli in the orofacial region into nociceptive signals in Vc. To examine this hypothesis, I propose to investigate how the PTPalpha-Src-Csk protein complex regulates 1) glutamate-mediated basal synaptic responses in Vc nociceptive neurons, 2) A- and C-fiber input-induced synaptic responses in Vc neurons, 3) the synaptic functions of Vc neurons in animals where the majority of C-afferent fiber innervations is removed. No such studies have yet been conducted in Vc, and so the proposed research promises to reveal novel molecular networks involved in the regulation of orofacial pain. ? ?
