Study of Activity-Dependent Sympathetic Sprouting

The role of the sympathetic nervous system (SNS) in regulating pain and inflammation has been well- established in animal models. In the clinic, sympathetic blockade is often used for managing neuropathic pain such as CRPS. The efficacy was evidenced by a recent clinical study showing dramatic and promising results using a catheter approach to provide longer lasting sympathetic blockade than is achieved by injection, in patients with intractable neuropathic pain. Mechanisms underlying SNS-mediated pain revealed by our group and our collaborators in the past 20 years include: activity associated SNS sprouting; generation of spontaneous activity; immune and inflammatory response; clustered firing of sensory neurons. We reported recently that persistent neuropathic pain is driven by active nerve regeneration. Our preliminary data also showed that sympathetic-mediated macrophage activation may be important in nerve regeneration as well as neuronal survival after nerve injury. Most interestingly, we found sympathetic-mediated immune/inflammatory responses, nerve regeneration, and pain behaviors could be reversed when the adjacent sciatic lymph node (LN) was removed, suggesting SNS-lymph node interactions may be critical for the development and possibly management of neuropathic pain. We hypothesize that sympathetic sprouting and its interactions with sensory neurons after nerve injury are neuroprotective and that sympathetic activation promotes cell survival but enhances pain due to increased nerve/axonal regeneration. We further hypothesize that SNS mediates immune responses, nerve regeneration, and cell survival by manipulation of macrophage activation, and, at least, partially, by interactions with adjacent lymph nodes. The hypothesis will be tested in three specific aims (SA): SA1: To determine whether sympathetic innervation is neuroprotective after peripheral nerve injury. SA2: To examine the relationships between cell death, regeneration, and macrophage subtypes in mouse models of neuropathic pain. SA3: To determine the role and function of adjacent lymph nodes (LN) in sympathetic regulation of immune response, nerve regeneration and cell survival. Our hypothesis proposes some novel concepts and represents a new direction for the study of sympathetic influences on pain and inflammation. The proposed studies will investigate and characterize, for the first-time, the sympathetic influences on neuronal survival, axonal regeneration at the level of sensory ganglia, and its interactions with lymph nodes in neuropathic pain conditions, which have high incidence, cost, and morbidity and for which effective treatments are often unavailable or unsatisfactory.