Descending modulation of chronic pain 

Research on the mechanisms of chronic pain has focused almost entirely on hypothesized deficits in pathways that process noxious information ascending from the periphery. However, growing evidence from both animal models and human studies indicates that chronic pain is often caused by defects in pain modulatory pathways, particularly those related to the affective components of pain. We are studying the roles of three key pathways: (1) Inhibitory inputs from the amygdala—a key structure in the limbic system involved in regulating the emotional aspects of pain—to the parabrachial complex, a nexus for modulation of the affective component of pain and of stress responses; (2) Serotonergic inputs from the rostroventral medulla—a key structure in descending pain modulation—to neurons in the spinal and trigeminal dorsal horn; (3) Inputs from cerebral cortex directly to the spinal and trigeminal dorsal horn. We are focused on developing therapeutic approaches that focus on these modulatory pathways.

Role of thalamic abnormalities in cognitive aspects of chronic pain 

Most patients with insults to the spinal cord or central nervous system suffer from excruciating, chronic pain that is largely resistant to treatment. Patients suffer most from spontaneous pain and its effects on cognition and affect. This condition affects a large percentage of spinal cord injury patients, as well as numerous patients with multiple sclerosis, stroke and other conditions. Using a rodent model, we discovered a novel mechanism of loss of inhibition within the thalamus that may predispose for the development of this chronic pain. The condition specifically affects “higher order”, paralemniscal thalamic nuclei that are involved in the affective and cognitive components of pain. Inhibition to these nuclei from GABA neurons in the zona incerta is dramatically reduced in chronic pain, resulting in abnormally high activity of these thalamic nuclei. We demonstrated that both the reduction in inhibition, and the increased thalamic activity, are causally related to the experience of chronic pain. We also developed a potential therapeutic approach in which inhibition from the zona incerta to the thalamus is restored—and chronic pain ameliorated.

Lasting effects of drug exposure on cortical activity 

Exposure to drugs, particularly during periods of brain development, is a significant risk factor for neurological and psychiatric disorders. We focus on understanding the mechanisms responsible for these conditions, and on developing strategies to ameliorate or even prevent their occurrence. Regular marijuana use during adolescence, but not adulthood, may permanently impair cognition and increase the risk for psychiatric diseases. This suggests that adolescence is a sensitive period because of the active development of cortical circuits and neuromodulatory systems at this age. We demonstrated, in mice, that chronic adolescent, but not adult, cannabinoid exposure permanently suppresses cortical oscillations and impairs working memory performance in adults. We are also studying the mechanisms by which exposure to opioids or nicotine, during early childhood, result in neurological and psychiatric disorders.