Research

Following upon our extensive earlier studies of the CNS circuits through which opioids exert their analgesic effects, our laboratory now examines the mechanisms through which tissue and nerve injury lead to persistent pain as well as the circuits through which pruritogens generate itch.

The hallmark of our work is a multidisciplinary approach to the problem, using molecular, neuroanatomical, pharmacological and behavioral analyses in wild type and genetically-modified mice, including knockouts and Cre- or reporter-expressing mice generated in our laboratory. By combining these studies with an analysis of the functional properties of molecularly-defined neurons, these studies examine the extent to which pain and itch circuits segregate or converge at the level of spinal cord interneurons and projection neurons. These studies have identified therapeutic targets that we are investigating in pharmacological studies using ligands identified in a major collaboration with colleagues who have generated novel ligands based on extensive in silico screening.

Taking a very different therapeutic approach, we also turned our attention to the possibility of overcoming the neurological consequences of peripheral nerve damage, by transplanting embryonic cortical GABAergic precursor cells into the spinal cord. We have demonstrated that the cells integrate synaptically and functionally into host neural circuits and can ameliorate the persistent pain and itch associated with nerve damage. And most recently, we have significantly expanded the scope of our studies. To examine the cortical circuits through which pain and itch percepts are generated, we are using calcium imaging of cortical neurons. These studies are also addressing the mechanism of action of different general anesthetics.

Paralleling these studies, we have extended the calcium imaging studies to spinal cord dorsal horn neurons, where we are now able to record, for months, the activity of large populations of neuronal and non-neuronal cells in awake, behaving mice.