Biomedical Sciences Graduate Program | University of California, San Francisco

Although there is considerable information about the mechanisms through which injury produces acute pain, much less is known about the long-term consequences of persistent injury. Pain is exacerbated, in part, because of a reorganization of spinal cord circuitry in the setting of persistent injury. Our laboratory uses neuroanatomical (light and electron microscopic immunocytochemistry), molecular and neuropharmacological/behavioral approaches to study the mechanisms through which these long-term changes are produced. One focus is the contribution of the primary afferent neurotransmitters, glutamate and substance P to these changes. Using immunocytochemistry, we can monitor internalization of neurotransmitter receptors as markers of activity of populations of "pain" responsive neurons. Using this approach we have determined the types of inputs that evoke the release of substance P and activate dorsal horn "pain" transmission neurons. A major goal is to determine the extent to which these changes occur when the injury persists, as it does in clinical pain conditions. Most recently we found that the magnitude and distribution of neurons that respond to substanceP (as indicated by receptor internalization) increase significantly in the setting of persistent inflammation.

We have also introduced molecular approaches to study the contribution of substance P to pain transmission. To this end, we have generated and are studying mice with a deletion of the gene that encodes substance P. Because the induction of long-term changes in pain processing involves activation of a variety of second messenger systems in dorsal horn neurons, we are also studying the consequences of their deletion. For example, we demonstrated that mice with a deletion of the gamma isoform of protein kinase C have a very discrete loss of peripheral nerve injury-induced persistent pain (so-called neuropathic pain). By contrast, acute pain responsiveness is intact in these mice, indicating that the processing of acute and persistent pain messages can be differentially regulated. In related studies in collaboration with the laboratory of David Julius we have studied mice with a deletion of the gene that encodes the vanniloid receptor (VR1), which is targeted by capsaicin, the active ingredient in hot peppers. Our results not only established that VR1 contributes to the heat pain sensitivity, but that injury-induced exacerbation of heat sensitivity is lost in the mutant mice.

To address the regulation of pain, we also study the mechanisms through which pain-relieving drugs, notably opioids, exert their effect. The latter studies continue our long-standing interest in the organization of pain control networks in the brainstem and spinal cord. In one series of studies we monitor expression of the Fos protein to follow the activity of neurons that are driven by noxious stimuli; the patterns of inhibition of Fos expression by opioids that act at different receptor subtypes can then be determined. We are also interested in the changes that occur in the CNS when tolerance to opioids develops. Evidence is accumulating that tolerance develops because of compensatory responses in CNS circuits and we have identified the spinal cord as a locus for these responses. Interestingly, features of the compensatory response are remarkably similar to the long-term changes that are produced by persistent injury. For example, antagonists of the NMDA receptor not only counteract exacerbated pain conditions, but also the development of tolerance and dependence. This observation is critical to developing approaches to overcome what appear to be largely deleterious consequences of persistent injury, so that better control of clinical pain conditions can be obtained. That is the long-term goal of the research in our laboratory.

Selected Publications