title: Virus-Mediated Knockdown of Nav1.3 in Dorsal Root Ganglia of STZ-Induced Diabetic Rats Alleviates Tactile Allodynia.
abstract: Diabetic neuropathic pain affects a substantial number of people and represents a major public health problem. Available clinical treatments for diabetic neuropathic pain remain only partially effective and many of these treatments carry the burden of side effects or the risk of dependence. The misexpression of sodium channels within nociceptive neurons contributes to abnormal electrical activity associated with neuropathic pain. Voltage-gated sodium channel Nav1.3 produces tetrodotoxin-sensitive sodium currents with rapid repriming kinetics and has been shown to contribute to neuronal hyperexcitability and ectopic firing in injured neurons. Suppression of Nav1.3 activity can attenuate neuropathic pain induced by peripheral nerve injury. Previous studies have shown that expression of Nav1.3 is upregulated in dorsal root ganglion (DRG) neurons of diabetic rats that exhibit neuropathic pain. Here, we hypothesized that viral-mediated knockdown of Nav1.3 in painful diabetic neuropathy would reduce neuropathic pain. We used a validated recombinant adeno-associated virus (AAV)-shRNA-Nav1.3 vector to knockdown expression of Nav1.3, via a clinically applicable intrathecal injection method. Three weeks following vector administration, we observed a significant rate of transduction in DRGs of diabetic rats that concomitantly reduced neuronal excitability of dorsal horn neurons and reduced behavioral evidence of tactile allodynia. Taken together, these findings offer a novel gene therapy approach for addressing chronic diabetic neuropathic pain.
authors.affiliation: Department of Neurology, Yale University School of Medicine, New Haven, Connecticut, United States of America; and Center for Neuroscience and Regeneration Research, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut, United States of America.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Tan
authors.affiliation: Department of Neurology, Yale University School of Medicine, New Haven, Connecticut, United States of America; and Center for Neuroscience and Regeneration Research, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut, United States of America.
authors.forename: Omar A
authors.initials: OA
authors.lastname: Samad
authors.affiliation: Department of Neurology, Yale University School of Medicine, New Haven, Connecticut, United States of America; and Center for Neuroscience and Regeneration Research, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut, United States of America.
authors.forename: Sulayman D
authors.initials: SD
authors.lastname: Dib-Hajj
authors.affiliation: Department of Neurology, Yale University School of Medicine, New Haven, Connecticut, United States of America; and Center for Neuroscience and Regeneration Research, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut, United States of America.
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Waxman
mesh_terms: D000818:Animals; D000229:Dependovirus / Q000235:genetics; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D005727:Ganglia, Spinal / Q000378:metabolism / Q000473:pathology; D006801:Humans; D006930:Hyperalgesia / Q000235:genetics / Q000628:therapy*; D062552:NAV1.3 Voltage-Gated Sodium Channel / Q000096:biosynthesis / Q000235:genetics*; D009437:Neuralgia / Q000235:genetics / Q000473:pathology / Q000628:therapy; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D059348:Peripheral Nerve Injuries / Q000235:genetics / Q000628:therapy*; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D051381:Rats
chemical_list: D062552:NAV1.3 Voltage-Gated Sodium Channel; D034741:RNA, Small Interfering; C478638:Scn3a protein, rat