Projects
MIGRAINE
Migraine has traditionally been thought of as a vascular disorder. However, it has become clearer in recent years that vascular changes cannot account for the pathophysiology of migraine and that maladaptive changes in the nervous system are more likely to contribute to this disorder. The exact changes in the nervous system contributing to migraine are not yet fully understood. The recent Global Burden of Disease Study by The Lancet (Vos et al 2012) found that migraine is the 3rd most prevalent disease in the world. Given this prevalence and the likely changes in the nervous system that lead to migraine, this makes migraine by far the most common neurological disorder. Unfortunately, less than 50% of migraine patients achieve adequate relief from currently available therapeutics. Studies in our laboratory are focused on mechanisms that mediate the pain of migraine. Using both in vitro and in vivo studies, we are focused on mechanisms leading to activation/sensitization of nociceptors innervating the cranial meninges including the potential contribution of non-neuronal cells (fibroblasts) to these processes. We are also interested in neuroplasticity that occurs across the central projections of these neurons the trigeminal nucleus caudalis and how this may contribute to lowered thresholds for headaches in migraine patients.
AMPK
A major focus of the lab is therapeutic development for pain. The lab has recently focused on Adenosine MonoPhosphate activated protein Kinase (AMPK) as a novel therapeutic target for alleviation of chronic pain. This work is based on our findings that insult to the peripheral nervous system causes a reorganization of signaling in mTOR and MAPK signaling pathways, both of which can be abrogated by AMPK activation. This project is unique for kinase targeting in pain because rather than blocking a specific kinase, the approach utilizes "agonists" of a kinase that acts as a negative regulator of multiple kinase pathways. Our agonist approach is multipronged including examination of existing drugs (metformin), natural products (resveratrol), tool compounds (A769662) and novel compound discovery. Projects on AMPK range from preclinical work to clinical trials in collaborating institutions.
PAIN MEMORY
Plasticity is at the very foundation of central nervous system function. Mechanisms of plasticity, such as long term potentiation, are thought to underlie learning and memory yet these same plasticity processes are likewise critical for pathological pain. We have discovered that molecules that are involved in maintaining long-term memory are also required for the transition to a chronic pain state. The anatomical location of changes in these molecules differs between learning and memory and chronic pain providing opportunities for targeted treatment approaches that can permanently reverse a chronic pain state. We are currently advancing these basic discoveries toward novel treatment avenues with the potential to revolutionize the way pain is treated.