Uncovering molecular mechanisms that underlie pain hypersensitivity in neuropathic pain may allow development of novel therapeutic strategies for treating this disorder. Non-coding RNAs that have been identified in mammalian cells regulate gene expression. Their expression is associated with the development of neurological diseases, but how non-coding RNA is causally linked to the diseases is unknown. We recently indentified a large, native, full-length non-coding RNA (2,574 nt) that is complementary to voltage-gated K+ channel (Kv) 1.2 mRNA in the dorsal root ganglion (DRG). Our data indicate that this Kv1.2 antisense (AS) RNA might be up-regulated via the activation of MZF-1 transcription factor in the injured DRG after peripheral nerve injury. Blocking this up-regulation might attenuate the induction of neuropathic pain. These preliminary findings suggest that DRG Kv1.2 AS RNA participates in the molecular mechanisms that underlie neuropathic pain. This proposal will further characterize native Kv1.2 AS RNA in the DRG and determine whether and how this AS RNA contributes to neuropathic pain.
In Specific Aim 1, we will examine the expression and distribution of Kv1.2 AS RNA in the DRG and define cytochemical characteristics of Kv1.2 AS RNA-containing DRG neurons in normal rats.
In Specific Aim 2, we will examine whether peripheral nerve injury produces an increase in expression of Kv1.2 AS RNA and its transcription factor MZF-1 in the DRG. Furthermore, we will examine whether Kv1.2 AS RNA is up- regulated as a result of MZF-1 binding to the consensus sequence on the Kv1.2 AS gene promoter in the injured DRG after peripheral nerve injury.
In Specific Aim 3, we will use a virally mediated gene transfer strategy to determine whether over-expression of Kv1.2 AS RNA specifically and selectively reduces expression of Kv1.2 mRNA and protein and total Kv current density in DRG neurons, increases DRG neuronal excitability, and leads to major symptoms of neuropathic pain in rats. We will also examine whether blocking nerve injury-induced up-regulation of Kv1.2 AS RNA in rats reverses nerve injury-induced reductions in DRG Kv1.2 expression and total Kv current density and attenuates nerve injury-induced abnormal DRG neuronal spontaneous activity and pain hypersensitivity. The proposed studies will provide major conceptual advances to our understanding of the molecular mechanism of neuropathic pain and might open a door for developing new strategies for treating neuropathic pain.
Neuropathic pain is poorly managed by standard drug therapy. Understanding mechanisms of pain hypersensitivity in neuropathic pain is important to improving clinical treatment and developing novel therapeutic strategies. The proposed studies will test novel hypothesis that peripheral nerve injury up- regulates the endogenous antisense RNA transcript of the Kv1.2 potassium channel in the injured dorsal root ganglion and that this up-regulation may contribute to the development and maintenance of neuropathic pain. The proposed studies may provide new strategies for clinical intervention of neuropathic pain.
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