My research objective is to understand the mechanisms that initiate and maintain chronic pain with the goal of developing therapeutic drug targets that outperform those currently available. I have developed a system for live cell Ca2+-imaging simultaneously from a multitude of cells in adult spinal cord slices. In my initial studies using this technique, I was able to show that glutamate-evoked Ca2+ signals are largely mediated by AMPA receptors (AMPAR) and are potentiated after neuropathic injury. I am currently extending these techniques to allow for genetically encoded Ca2+-imaging in neuronal and non-neuronal cells that contribute to pain neurotransmission.
- AMPA receptor plasticity that contributes to chronic pain. We have made a striking observation that inflammation produces an increase in dorsal horn calcium permeable (CP)-AMPAR expression and function, a shift that persists at least 21d after injury. This suggests that CP-AMPARs drive the induction and/or maintenance of long-lasting central sensitization that may result in susceptibility to the development of chronic pain. These findings along with studies from the ventral tegmental area that demonstrate a shift from conventional to non-conventional (GluN3-containing) NMDAR expression after cocaine injection that is necessary for the expression of cocaine-evoked AMPAR plasticity provide the premise for this research focus: to test the hypothesis that inflammation increases CP-AMPARs in pronociceptive dorsal horn neurons that then initiates the development of LCS (and thus chronic pain) by a GluN3-dependent mechanism.
- Microglial signaling in neuropathic pain. We recently published our findings that the complement 3a receptor (C3aR1) is specifically expressed on spinal microglia and its expression increases after nerve injury. We demonstrated that selective targeting and activation of C3aR1 on spinal microglia (using the neuropeptide TLQP-21) produced hyperalgesia and increased microglial [Ca2+]i. Our findings suggest that TLQP-21 and the endogenous immune mediator C3a lead to activation of microglial C3aR1s. However, the intracellular signaling mechanisms downstream of C3aR1 activation that leads to neuropathic pain are unknown. These findings along with studies from peripheral immune cells demonstrating C3aR-mediated cytokine production provide the premise for this research focus. I am currently doing studies to test the hypothesis that after neuropathic injury, C3aR1 activation of spinal microglia drives neuropathic pain.