Funded Projects

Chronic pain diminishes the quality of life for millions of patients, and new drugs that have better efficacy and/or fewer side effects are needed. A promising target is the sphingosine-1-phosphate (S1P) receptor system, which mediates central nervous system (CNS) neuromodulatory functions. FTY720-phosphate, the active metabolite of FTY720 (FTY), acts as an agonist at four of the five S1P receptors (S1P1, 3, 4, 5). We propose that the S1P1 receptor is a target for treatment of neuropathic pain. We will test whether S1P1 receptors mediate anti-hyperalgesic effects in a mouse neuropathic pain model. The specific aims are to: 1) determine the role of S1P1Rs in alleviation of neuropathic pain by S1PR ligands; 2) determine the role of FTY-induced S1PR adaptation in FTY-mediated reversal of neuropathic pain; and 3) determine the role of S1P and S1P1 receptors in spinal glia in CCI-induced neuropathic pain and its reversal by FTY.

Many chronic pain conditions are dependent upon activity of the sympathetic nervous system. Sympathetic blockade is used clinically in chronic pain conditions, but the clinical and preclinical evidence for this practice is incomplete. We propose that certain pathological pain conditions require intact sympathetic innervation of the sensory nervous system at the level of the dorsal root ganglion (DRG) and that release of sympathetic transmitters enhances local inflammation and leads to pain. Our preliminary data show large, rapid, and long-lasting reduction of pain behaviors and inflammatory responses following a"microsympathectomy" (mSYMPX) in both neuropathic and inflammatory pain models. Our aims are to: 1) characterize the effects of mSYMPX on pain and on local inflammation in the DRG; 2) explore the molecular mechanisms for sympathetic regulation of inflammatory responses in the DRG; and 3) assess the functional role of sympathetic transmitters in the sympathetically mediated inflammatory responses in the DRG.

Efforts to identify non-opioid analgesics for treatment of chronic pain have identified a protein, carbonic anhydrase-8 (CA8), in pain-sensing nerve cells in the spinal cord (dorsal root ganglion cells) whose expression regulates analgesic responses. Gene therapy delivering CA8 to dorsal root ganglion cells through clinically relevant routes of administration functions as a “local anesthetic” that induces long-lasting pain relief in animal models of chronic pain. This project will further develop CA8 gene therapy with the goal of treating chronic knee osteoarthritis pain. It will assess several gene therapy constructs to determine the doses needed, safety, efficacy, and specificity to nerve cells for each construct. It will then select the safest and most effective construct that can be administered via the least invasive route for further development. The project will include all steps necessary to identify one candidate gene therapy construct that will be suitable to begin clinical trials in patients with chronic knee osteoarthritis pain.