Neuromolecular Basis for Pain in Burn Injury

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 DESCRIPTION (provided by applicant): There is a very substantial need, both within the VA, and within the U.S. population, for more effective treatments for pain associated with burn injury. Our laboratory possesses unique expertise in the study of sodium channels and their binding partners as related to pain, and in dendritic spine dysgenesis as related to pain. We have developed and calibrated burn injury pain models in rodents, and have unequivocally indicted sodium channel Nav1.7 as playing a major role in pain after burn injury. We also have developed a unique gene therapy platform and have shown that we can knockdown specific sodium channel subtypes and ameliorate pain after nerve injury. Targeting of novel molecules identified in our pre-clinical burn injury studies usinga gene therapy approach, and a small molecule compound already approved for human use for other neurological indications, holds promise for more effective treatment options for Veterans with burn injuries. In this study: We will assess the therapeutic potential of gene therapy knockdown of Nav1.3 in burn injury by building upon our previous findings that Nav1.3 up-regulation in DRG and spinal cord dorsal horn contributes to neuropathic pain, and that knockdown of Nav1.3 results in attenuation of pain due to traumatic nerve injury. We will examine whether disruption of contactin trafficking attenuates pain after burn injury by building upon our demonstration that: a) contactin-1 forms a complex with Nav1.3 sodium channels and facilitates insertion of functional channels within the cell membrane; and b) contactin-1 is up-regulated following axotomy and co-localizes with this channel in axonal tips within neuromas. We will explore the therapeutic potential of Nav1.6 knockdown in the treatment of pain via Nav1.6- siRNA in our burn injury model as a follow up to our findings that afferent signal transmission of mechanical pain after burn injury is not critically dependent on Nav1.8 or Nav1.7, and that Nav1.6 is not only expressed in DRG neurons but also has biophysical attributes that poise it to contribute to repetitive action potential firing. We will test whethe targeting the Rac1 pathway through systemic administration of FDA-approved PAK1 inhibitor FK228, can block dendritic spine dysgenesis on dorsal horn neurons and ameliorate neuropathic pain after burn injury as a follow up to our demonstration that Rac1-mediated spine dysgenesis contributes to neuropathic pain following second-degree burn injury. All of our studies are aimed at development of new therapies for chronic pain associated with burn injury.