Research in the laboratory focuses on the biology of sensory neurons after injury or in neurological disease. These problems are associated with peripheral neuropathy and can lead to poor sensation, chronic pain, or abnormalities in gait. The focus of our research is to understand how sensory neurons that convey sensory information to the spinal cord are altered in disease. The sensory neurons are powerfully regulated by endogenous neurotrophic factors and our overall objective is to understand how neurotrophins may improve sensory impairments caused by injury or disease. Our research emphasis is related to 2 different diseases: fibromyalgia and diabetic neuropathy.
Our long-range goal is to understand the cellular and molecular components within the peripheral nervous system that are important to hyperalgesia in females. Secondary hyperalgesia is a prominent feature in female pain syndromes including fibromyalgia. Our studies have focused on a model that develops chronic mechanical secondary hyperalgesia and utilizes acid injection into skeletal muscle to induce hyperalgesia in adjacent body regions. Our results demonstrate that the secondary hyperalgesia can be prevented by intramuscular injection of neurotrophin-3 (NT-3). Because of the importance of gender in widespread pain syndromes associated with secondary hyperalgesia, it is plausible that estrogen strongly influences the development of these conditions. Our studies reveal that estrogen replacement completely prevents the appearance of acid-induced secondary hyperalgesia, similar to NT-3 treatment. Thus, these results suggest that important relationships exists between estrogen and NT-3 that may be essential for the anti-nociceptive actions of estrogen that mimics aspects of fibromyalgia. Ongoing studies are testing whether estrogen prevents the development of acid induced secondary hyperalgesia. Other experiments are testing whether estrogen (and/or acid) acts by regulating NT-3 production in muscle and if estrogen (and/or acid) modulates sensory innervation of muscle. Finally, we are interested in whether exercise intervention can prevent or reverse widespread pain induced by acid. Collectively, these studies will provide new information about anti-nociceptive actions of neurotrophins, estrogen and exercise on peripheral neural systems involved in the development of chronic, widespread pain relevant to fibromyalgia. This projects utilizes several models to study the trophic support of neurons following perturbation in vivo, and to explore the extent of NT-3's therapeutic effects: NT-3 transgenic, NT-3 null mutant, and hereditary mutant mice that undergo degeneration of NT-3-dependent sensory neurons.
The mechanisms that lead to painful or insensate symptoms in diabetic neuropathy (DN) are poorly understood. Many variables likely play a role in the development of these diverse symptoms, including reduced neurotrophic supply, abnormal insulin support, and oxidative stress mediated through advanced glycation endproduct (AGE) formation. These symptoms may also underlie peripheral axon damage amongst select sensory neuronal subpopulations. Our overall goal is to understand the etiology of painful and/or insensate complications of DN in relation to insulin support, oxidative stress, and peripheral axon degeneration. We propose that unique genetic differences underlie the differential progression and severity of diabetic neuropathy. Exploring these genetic differences will help identify mechanisms involved in the pathogenesis of diabetic neuropathy. Ongoing studies are focused on understanding the progression of painful and insensate neuropathy in type 1 and type 2 models of diabetes. Other studies are testing whether insulin support plays a critical role in the progression of painful or insensate neuropathy amongst these variant models of diabetes. Certain studies are examining the role of AGEs and oxidative stress in the development of painful or insensate neuropathy in these diabetes models. Finally, much of our focus is on whether differential damage to axons that innervate skin is important factor in developing painful or insensate diabetic neuropathy. Collectively, these studies will identify possible mechanisms responsible for the variable progression of symptoms experienced within human patients and identify new therapeutic targets aimed at the severity of symptoms amongst diabetic patients.