Reduction of voltage gated sodium channel protein in DRG by vector mediated miRNA reduces pain in rats with painful diabetic neuropathy

Subcutaneous inoculation of the miRNA-expressing HSV vector into the feet of diabetic rats to transduce DRG resulted in a reduction in NaVα subunit levels in DRG neurons, coincident with a reduction in cold allodynia, thermal hyperalgesia and mechanical hyperalgesia.These data support the role of increased NaVα protein in DRG in the pathogenesis of pain in diabetic neuropathy, and provide a proof-of-principle demonstration for the development of a novel therapy that could be used to treat intractable pain in patients with diabetic neuropathy.Pain is a common complication of diabetic neuropathy that, despite substantial advances in understanding of pathophysiology, remains relatively refractory to treatment with available agents [1]. In rats with streptozotocin (STZ) induced diabetes and painful neuropathy, an increase in the alpha (pore-forming) subunit of voltage gated sodium channel isoform 1.7 (NaV1.7) in primary sensory afferent neurons of the dorsal root ganglia (DRG) has been reported [2], a change that correlates with increased amplitude and negative shift of the activation of tetrodotoxin (TTX)-sensitive current in those neurons. A potential pathogenic role for NaV1.7 in the development of pain in this syndrome is supported by the observation that gain of function mutations in NaV1.7 cause inherited spontaneous neuropathic pain syndromes primary erythermalgia [3,4] and paroxysmal extreme pain disorder [5].In previous studies we have constructed a series of herpes simplex virus (HSV)-based gene transfer vectors that effectively transduce DRG in vivo from skin inoculation, and have used these vectors to express inhibitory neurotransmitters [6-8] or neurotrophic factors [9-11]. In order to explicitly test the role of increased levels of NaV in DRG in the pathogenesis of pain in PDN, we constructed a non-replicating herpes simplex virus (HSV)-based vector to reduce NaVα protein in DRG, and compared the effect of NaVα subunit knockdown on pain-related behaviors i