New Target Identification for Nervous System Repair

Sodium Channel Isoforms in Neuropathic Pain

In our search for better treatments for neuropathic pain, we are investigating a range of voltage gated sodium channels that have been implicated in painful neuropathies. For example, our investigations of gain of function mutations in Nav1.8 in patients with painful neuropathy revealed altered physiology and kinetics that causes hyperexcitability and spontaneous firing of DRG neurons (Han et al., 2015). Our investigations of a novel mutation in Nav1.9 in a patient with small fiber neuropathy also revealed an effect on DRG neuron hyperexcitability and provided insight into the basis for the neuropathic pain experienced by this patient while validating Nav1.9 as a new target for therapy (Han et al., 2015). Our ongoing studies of new mutations in people with rare genetic diseases as well as common neuropathies and polymorphisms are contributing to increased understanding of voltage gated sodium channels and their role in pain pathologies, while shaping efforts toward improved therapies (Estacion et al., 2015; Tanaka et al., 2016).

Nav1.5 and Astrogliosis

Damage to the spinal cord activates astrocytes to become reactive, a process known as astrogliosis that leads to glial scarring. Controversy exists on whether glial scarring is beneficial or deleterious to the repair of damaged spinal cord. Our examination of post-mortem tissue from people with disabling secondary progressive multiple sclerosis revealed abnormal levels of sodium channel Nav1.5 in reactive astrocytes at the borders of, and within, active and chronic multiple sclerosis lesions. In contrast, Nav1.5 was detectable at very low levels in astrocytes within normal-appearing white matter and in normal control brain (Black JA et al., 2010). To understand the significance of Nav1.5 in reactive astrocytes, we created an in vitro model of mechanical injury to astrocytes. Our studies in this model showed that blockade of Nav1.5 renders a protective effect in that there is attenuation of injury-induced migration and proliferation of astrocytes, a critical precursor to astrogliosis (Pappalardo LW et al., 2014). To further explore the role of Nav1.5, we are utilizing gene knockout technology to examine the blockade of Nav1.5 in conditions of astrogliosis and glial scarring following damage to the spinal cord in vivo.

Dendritic Spines in Neuropathic Pain and Spasticity

Neuronal hyperexcitability is a substrate for many nervous system pathologies. We have evidence that hyperexcitable neurons exhibit structural changes that are characteristic of their hyperexcitable state. For example, dendritic spines of sensory neurons in neuropathic pain models of spinal cord injury, diabetic neuropathy, and burn injury, reveal striking reorganization that correlates with pain and hyperexcitability (Tan and Waxman, 2015; Tan et al., 2013; Tan et al., 2012). Such neurons display higher densities of distinct mushroom shaped spines closer to their cell bodies compared to their normal counterparts. A similar examination of spinal cord motor neurons after spinal cord injury also reveals plasticity in dendritic spine profiles that correlate strongly with motor neuron hyperexcitability and reflex dysfunction (spasticity) (Bandaru et al., 2015). Our findings suggest that targeting mechanisms that affect dendritic spine structures may represent a novel approach to treating pain and spasticity, and support the notion that dendritic spines serve as structural biomarkers of neuronal hyperexcitability (Zhao et al., 2016).


Han C, Estacion M, Huang J, Vasylyev D, Zhao P, Dib-Hajj SD, Waxman SG. Human Nav1.8: enhanced persistent and ramp currents contribute to distinct firing properties of human DRG neurons. J Neurophysiol. 2015 May 1;113(9):3172-85.

Han C, Yang Y, de Greef BT, Hoeijmakers JG, Gerrits MM, Verhamme C, Qu J, Lauria G, Merkies IS, Faber CG, Dib-Hajj SD, Waxman SG. The Domain II S4-S5 Linker in Nav1.9: A Missense Mutation Enhances Activation, Impairs Fast Inactivation, and Produces Human Painful Neuropathy. Neuromolecular Med. 2015 Jun;17(2):158-69.

Han C, Estacion M, Huang J, Vasylyev D, Zhao P, Dib-Hajj SD, Waxman SG. Human Nav1.8: enhanced persistent and ramp currents contribute to distinct firing properties of human DRG neurons. J Neurophysiol. 2015 May 1;113(9):3172-85.

Tanaka BS, Zhao P, Dib-Hajj FB, Morisset V, Tate S, Waxman SG, Dib-Hajj SD. A gain-of-function mutation in Nav1.6 in a case of trigeminal neuralgia. Mol. Med. 2016 Aug 3;22 EPub. 


Black JA, Newcombe J, Waxman SG. Astrocytes within multiple sclerosis lesions upregulate sodium channel Nav1.5. Brain. 2010 Mar; 133(Pt 3):835-46.

Pappalardo LW, Samad OA, Black JA, Waxman SG. Voltage-gated sodium channel Nav 1.5 contributes to astrogliosis in an in vitro model of glial injury via reverse Na+ /Ca2+ exchange. Glia. 2014 Jul;62(7):1162-75.

Pappalardo LW, Liu S, Black JA, Waxman SG. Dynamics of sodium channel Nav1.5 expression in astrocytes in mouse models of multiple sclerosis. Neuroreport. 2014 Oct 22;25(15):1208-15.

Tan AM, Waxman SG. Dendritic spine dysgenesis in neuropathic pain. Neurosci Lett. 2015 Aug 5;601:54-60.

Tan AM, Samad OA, Liu S, Bandaru S, Zhao P, Waxman SG. Burn injury-induced mechanical allodynia is maintained by Rac1-regulated dendritic spine dysgenesis. Exp Neurol. 2013 Oct;248:509-19.

Bandaru SP, Liu S, Waxman SG, Tan AM. Dendritic spine dysgenesis contributes to hyperreflexia after spinal cord injury. J Neurophysiol. 2015 Mar 1;113(5):1598-615.

Tan AM, Samad OA, Fischer TZ, Zhao P, Persson AK, Waxman SG. Maladaptive dendritic spine remodeling contributes to diabetic neuropathic pain. J Neurosci. 2012 May 16;32(20):6795-807.

Zhao P, Hill M, Liu S, Chen L, Bangalore L, Waxman S, and Tan A. Dendritic Spine Remodeling Following Early and Late Rac1-Inhibition after Spinal Cord Injury: Evidence for a Pain Biomarker. J Neurophysiol 2016.