Current Research and Scholarly Interests
My laboratorys research is centered on achieving a better understanding of and improving the management of pain. This work can be roughly divided into two distinct parts: pain physiology and diagnosis and pain therapy. In terms of pain diagnosis, my laboratory is focused on identifying biomolecular and physiological markers that are indicative of different pain pathologies and can be directive in choosing therapies for that pain state. Thus, we are examining changes in pain nerve (nociceptor) gene expression in skin and nerve tissue. For example, we have recently investigated changes in expression of voltage gated sodium channels under inflammatory and post-incisional conditions. We have also studied the release of neuropeptide, cytokine, and trophic biomarkers into skin and into the spinal epidural space during different pain and inflammatory states in rodents and humans and the effects of treatments on this release. This biomarker methodology is very useful in the process of analgesic and anti-inflammatory therapy development.
Pain is primarily subtended by two distinct nociceptor types. When activated, the thinly myelinated A-delta pain fibers create the sensation of sharp, pricking pain, whereas activation of unmyelinated C fibers produces a burning or aching sensation. One or the other type of nociceptor is thought to be dominant in different human pain states. Several years ago, we developed simple methods for differentiating pain or responses evoked by the activation of A-delta or C fiber nociceptors in humans and animals. Using a laser-based stimulation system, we are performing experiments examining both electrophysiological and biochemical responses to these two pain types. Some of this work is done in rodents, wherein we perform both single unit nociceptor recordings, as well as recordings from nociceptive neurons in the spinal cord. We are also using a combination of cortical evoked potential responses to laser pulsed pain stimuli as well as functional magnetic resonance imaging (fMRI) of the brain of volunteers (and eventually patients) to determine the cortical representation of these A-delta and C fiber mediated pain. The hope is that after defining these brain maps for the two pain physiologies, we will be better able to determine the physiology of clinical pain of unknown nociceptor dominance.
Gene Therapy for Pain
Over the last 10 years, we have developed herpes simplex I-based vectors to carry analgesic genes, antisense, or siRNAs into nociceptors. For example, we have developed a recombinant vector which, when placed on or in tissue of rodents or monkeys, is picked up by the nociceptors innervating that tissue and transported along the peripheral nerve back to the cell bodies of these nerve fibers. The inserted transgene is then expressed. For example, nociceptors exposed to vectors encoding human enkephalins begin to make this endorphin-like peptide. These enkephalins selectively inhibit the nociceptors exposed to these viruses for at least 20 weeks (in monkeys). Thus, this method may provide a means of long-term treatment of chronic, localized pain conditions. To this end, we are developing the bases for clinical trials wherein our vector is applied to painful metastatic sites of cancer patients.
In summary, we perform laboratory and clinical research in the area of pain and analgesia. Some of this work centers on improving our understanding of the mechanisms underlying clinical pain states, hopefully leading to more accurate diagnosis and treatment. It also centers on the development of a completely new way to treat chronic pain, namely gene therapy. The environment in which these studies are performed, that of the Department of Anesthesia and the Pain Working Group of the Neuroscience Institute at Stanford, is an ideal one in which to do this work.