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.
Highlights
Diabetic neuropathic pain is a chronic and often intractable condition with limited clinical treatment options and represents a major unmet medical need [1]
We have previously demonstrated that direct injection into dorsal root ganglion (DRG) of adeno-associated virus (AAV) vectors expressing small-hairpin RNA (shRNA) against Nav1.3 resulted in significant knockdown of Nav1.3 expression and reduced nerve injury–induced neuropathic tactile allodynia [5]
We quantified the percentage of green fluorescent protein (GFP)-positive neuronal profiles in tissue sections of L4-L5 DRGs, which contribute to the innervation of the hindquarters and hindpaw dermatomes
Summary
Diabetic neuropathic pain is a chronic and often intractable condition with limited clinical treatment options and represents a major unmet medical need [1]. A large body of work demonstrates that abnormal sodium channel expression in dorsal root ganglion (DRG) neurons produces hyperexcitability in these neurons that underlies neuropathic pain [2,3]. Nav1.3 is normally undetectable in adult DRG neurons, expression of this sodium channel subtype is upregulated in these cells after axotomy (that is, nerve transection) and chronic constriction injury models of neuropathic pain [4,6,7,9,10,11]. The advent of gene therapy has recently shown promise in the treatment of neuropathic pain, the use of viral-mediated delivery of small-hairpin RNA (shRNA) constructs to knockdown target proteins [5,14]. Gene therapy offers three major advantages: target specificity (for example, blocking of specific sodium channel isoforms), reduced incidence of adverse events or side effects, and thera-
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call