This research proposal encompasses four inter-related projects that seek to do the following.
Specific Aims I and II: Delineate mechanisms of, and identify effective therapies for, chronic pain resulting from traumatic nerve injury and limb amputation. Neuromas resulting from traumatic nerve injury and traumatic limb amputation can act as sites of abnormal ectopic impulse generation, which are linked to neuropathic pain. In many cases, neuroma-induced pain is not responsive to existing medications. We have shown that sodium channel Nav1.3 accumulates in both painful human neuromas and in experimental neuromas. The biophysical characteristics of Nav1.3 support its contribution to ectopic impulse generation in neuromas. In translational Aim I, we will build upon our viral- mediated shRNA (AAV-shRNA) knockdown of Nav1.3 in rat DRG in vivo and test the hypothesis that AAV- shRNA-Nav1.3 attenuates neuroma-induced pain. Multiple studies have indicated a contribution of channel isoform Nav1.7 to neuropathic pain. Nav1.7 accumulates in injured axon tips within human neuromas and in experimental neuromas, and has been genetically linked to human pain. As an alternative to targeting Nav1.3, Aim II will test AAV-shRNA mediated knockdown of Nav1.7 toward attenuation of neuroma-induced pain.
Specific Aim III : Decipher specific sodium channel isoforms responsible for action potential conduction along nociceptive nerve fibers. In this mechanistic aim, we will assess the contribution of Nav1.7, Nav1.8 and Nav1.3 to electrogenesis in small-diameter axons of DRG neurons. We have recently developed the capability to patch-clamp small diameter (<1mm) DRG neurites in vitro and demonstrated that TTX-S and TTX-R sodium conductances are sequentially activated during action potentials. To advance our understanding of axonal electrogenesis, a logical next step is to identify the underlying channel subtypes and assess their contribution to excitability in nociceptive axons, as we propose in this specific aim. In addition, we will assess the functional effect of gain- of-function variants of Nav1.7 and Nav1.8 that are known to be associated with chronic pain syndromes in humans, on electrogenesis within the axonal compartment, utilizing our DRG culture/patch-clamp system.
Specific Aim I V: Determine the contribution of aberrant sodium channel expression in SCI-induced spasticity. Spasticity after SCI has been classically thought to be a result of enhanced synaptic transmission along the spinal reflex pathways as well as loss of inhibition. However, studies at the circuit level, and computer simulation studies, suggest a contribution of increased intrinsic excitability of motor neurons and altered expression of sodium channels within motor neurons to spasticity after SCI. We have demonstrated upregulated expression of Nav1.3 within dorsal horn neurons after SCI and several investigators have reported upregulated expression of sodium channels in spinal and facial motor neurons following peripheral axotomy. Additionally, we have shown that Nav1.8 is mis-expressed in human CNS neurons, cerebellar Purkinje neurons) in patients with multiple sclerosis and in mice with EAE. In this mechanistic/translational aim, we will use molecular, patch-clamp, and knockdown methods to test the hypothesis that dysregulated sodium channel expression in motor neurons contributes to spasticity following SCI, and will determine whether knockdown of such dysregulated channels ameliorates spasticity.

Public Health Relevance

Chronic pain resulting from injury to peripheral nerves, and spasticity due to spinal cord injury (SCI), are major health concerns within the VA. Clinically significant pain and spasticity affects approximately 50-80% of patients with nerve injuries. Currently available treatments for pain and spasticity due to nerve injuries are often not effective or are only partially effective, and thus represent an unmet medical need within the VA. The goal of our research is to explore novel therapies and delineate underlying mechanisms of neuronal hyperexcitability associated with chronic pain and spasticity.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Neurobiology C (NURC)
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VA Connecticut Healthcare System
West Haven
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Dib-Hajj, Sulayman D; Geha, Paul; Waxman, Stephen G (2017) Sodium channels in pain disorders: pathophysiology and prospects for treatment. Pain 158 Suppl 1:S97-S107
Akin, Elizabeth J; Solé, Laura; Dib-Hajj, Sulayman D et al. (2015) Preferential targeting of Nav1.6 voltage-gated Na+ Channels to the axon initial segment during development. PLoS One 10:e0124397
Tan, Andrew M; Waxman, Stephen G (2015) Dendritic spine dysgenesis in neuropathic pain. Neurosci Lett 601:54-60
Han, Chongyang; Yang, Yang; de Greef, Bianca T A et al. (2015) The Domain II S4-S5 Linker in Nav1.9: A Missense Mutation Enhances Activation, Impairs Fast Inactivation, and Produces Human Painful Neuropathy. Neuromolecular Med 17:158-69
Estacion, M; Vohra, B P S; Liu, S et al. (2015) Ca2+ toxicity due to reverse Na+/Ca2+ exchange contributes to degeneration of neurites of DRG neurons induced by a neuropathy-associated Nav1.7 mutation. J Neurophysiol 114:1554-64
Bandaru, Samira P; Liu, Shujun; Waxman, Stephen G et al. (2015) Dendritic spine dysgenesis contributes to hyperreflexia after spinal cord injury. J Neurophysiol 113:1598-615
Han, Chongyang; Estacion, Mark; Huang, Jianying et al. (2015) Human Na(v)1.8: enhanced persistent and ramp currents contribute to distinct firing properties of human DRG neurons. J Neurophysiol 113:3172-85
Huang, Jianying; Han, Chongyang; Estacion, Mark et al. (2014) Gain-of-function mutations in sodium channel Na(v)1.9 in painful neuropathy. Brain 137:1627-42
Dib-Hajj, Sulayman D; Waxman, Stephen G (2014) Translational pain research: Lessons from genetics and genomics. Sci Transl Med 6:249sr4
Waxman, Stephen G; Merkies, Ingemar S J; Gerrits, Monique M et al. (2014) Sodium channel genes in pain-related disorders: phenotype-genotype associations and recommendations for clinical use. Lancet Neurol 13:1152-1160