Study of Activity Dependent Sympathetic Sprouting

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 DESCRIPTION (provided by applicant): Clinically, many chronic pain conditions are worsened by or even dependent upon activity of the sympathetic nervous system. Sympathetic blockade is often used clinically in chronic pain conditions, but the clinical and preclinical evidence for thi practice has been contradictory and incomplete. However, a very recent study showed dramatic and promising results using a catheter approach to provide longer lasting sympathetic blockade than is achieved by injection, in patients with intractable pain. Most preclinical research has focused on the abnormal interactions between the sensory and sympathetic nervous systems in models of chronic pain. Based on our preliminary data and recent publications, we propose that the initiation and persistence of certain pathological pain conditions requires intact sympathetic innervation of the sensory nervous system at the level of the sensory ganglion, and that release of sympathetic transmitters enhances local inflammation of the sensory ganglia and leads to pain. Local inflammatory responses in the sensory ganglia occur even after remote nerve injuries, so this phenomenon is important to understanding many types of chronic pain conditions. Our preliminary data show large, rapid, and long-lasting reduction of pain behaviors and inflammatory responses following a "microsympathectomy" (mSYMPX) in both neuropathic and inflammatory pain models. This procedure involves cutting the gray rami (sympathetic postganglionic fibers) to only the lumbar sensory ganglia. mSYMPX avoids many effects of chemical or surgical sympathectomy used in most previous studies, such as sympathetic denervation of primary and secondary immune tissues. Since sympathetic innervation of some of these tissues is anti-inflammatory, global sympathectomy may have obscured pro-inflammatory effects at the sensory ganglion level. The mSYMPX method is also more clinically relevant since patients often receive local sympathetic blocks. The hypothesis will be tested in 3 specific aims: 1) To characterize the effects of mSYMPX on the development and persistence of pain and on local inflammation in the DRG. The effects of mSYMPX after pain is well-established will be tested, and its effects on infiltration of immune cells in the sensory ganglia examined with microscopy. 2) To explore the molecular mechanisms for sympathetic regulation of inflammatory responses in the DRG. Effects of mSYMPX on local cytokine levels and immune cell polarization will be examined, based on our preliminary finding that the pro-inflammatory cytokines induced by a pain model are normalized by mSYMPX. 3) To assess the functional role of sympathetic transmitters in the sympathetically mediated inflammatory responses in the DRG. Using novel methods developed in our laboratory for locally perfusing the sensory ganglia and locally knocking down specific molecules, we will examine the roles of different noradrenergic and ATP receptors in mediating the pro-inflammatory role of the sympathetic fibers. The proposed experiments will elucidate a novel mechanism for sympathetically maintained pain with relevance to several chronic pain conditions with inflammatory component.