In Vivo Genetic Manipulation of Neuronal Excitability

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DESCRIPTION (provided by applicant): Despite many years of research, the mainstays of clinical treatment of pain remain highly problematic. High dose opiate analgesics have numerous side effect, induce tolerance and dependence and have significant abuse potential. New knowledge and technologies, however, may allow for entirely new approaches to the management of chronic pain. It has recently been established that there are 12 or more different isoforms of neuronal sodium channels, which are critical to these neurons' ability to convey information. One isoform in particular, Nav1.7, appears to be selectively present in neurons that carry pain information from the periphery to the central nervous system. Furthermore, levels of these channels, as well as their location on these neurons, change dramatically during chronic pain states, implying that they are important in establishing and/or maintaining these pain states. Thus, an examination of Nav1.7 channel function may be significant in designing new approaches to the treatment of chronic pain. In order to establish the importance of this sodium channel in pain, virally directed gene transfer will be used to decrease or eliminate expression of the gene for Nav1.7 selectively in those neurons that carry pain information. Herpes viral vectors have been previously used to insert novel transgenes into these neurons, and to decrease synthesis of endogenous proteins, but this approach has never been applied to sodium channels. Thus, a herpes virus encoding an antisense sequence for the Nav1.7 channel gene will be used to knock-down production of this channel, so that immunochemical, behavioral, and electrophysiological experiments can be conducted in order to examine the contribution of Nav1.7 in pain biology. In this way, it should become clear whether or not this channel represents a potential target for the development of new pharmaceutical tools. Another implication of this work, however, is that this approach may in itself provide a means of therapy, and it may be possible to use herpes vectors to inhibit production of endogenous Nav1.7 channels in chronic pain patients, providing a long-term genetic therapy for their pain.