title: Vector-mediated release of GABA attenuates pain-related behaviors and reduces Na(V)1.7 in DRG neurons.
abstract: Pain is a common and debilitating accompaniment of neuropathy that occurs as a complication of diabetes. In the current study, we examined the effect of continuous release of gamma amino butyric acid (GABA), achieved by gene transfer of glutamic acid decarboxylase (GAD67) to dorsal root ganglia (DRG) in vivo using a non-replicating herpes simplex virus (HSV)-based vector (vG) in a rat model of painful diabetic neuropathy (PDN). Subcutaneous inoculation of vG reduced mechanical hyperalgesia, thermal hyperalgesia and cold allodynia in rats with PDN. Continuous release of GABA from vector transduced cells in vivo prevented the increase in the voltage-gated sodium channel isoform 1.7 (Na(V)1.7) protein that is characteristic of PDN. In vitro, infection of primary DRG neurons with vG prevented the increase in Na(V)1.7 resulting from exposure to hyperglycemia. The effect of vector-mediated GABA on Na(V)1.7 levels in vitro was blocked by phaclofen but not by bicuculline, a GABA(B) receptor effect that was blocked by pertussis toxin-(PTX) interference with Gα((i/o)) function. Taken in conjunction with our previous observation that continuous activation of delta opioid receptors by vector-mediated release of enkephalin also prevents the increase in Na(V)1.7 in DRG exposed to hyperglycemia in vitro or in vivo, the observations in this report suggest a novel common mechanism through which activation of G protein coupled receptors (GPCR) in DRG neurons regulate the phenotype of the primary afferent.
authors.affiliation: Department of Neurology, University of Michigan and VA Ann Arbor Healthcare System, Ann Arbor, MI, USA.
authors.forename: Munmun
authors.initials: M
authors.lastname: Chattopadhyay
authors.forename: Marina
authors.initials: M
authors.lastname: Mata
authors.forename: David J
authors.initials: DJ
authors.lastname: Fink
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D002478:Cells, Cultured; D003929:Diabetic Neuropathies / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D005260:Female; D005727:Ganglia, Spinal / Q000378:metabolism*; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006930:Hyperalgesia / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D062556:NAV1.7 Voltage-Gated Sodium Channel; D009474:Neurons / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018139:Simplexvirus / Q000235:genetics; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism*; D013311:Streptozocin; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D062556:NAV1.7 Voltage-Gated Sodium Channel; C503480:Scn9a protein, rat; D015222:Sodium Channels; D005680:gamma-Aminobutyric Acid; D013311:Streptozocin