Dorsal Root Ganglion Application of Muscimol Prevents Hyperalgesia and Stimulates Myelin Protein Expression After Sciatic Nerve Injury in Rats

Abstract

Peripheral nerve injuries may result in debilitating pain that is poorly responsive to conventional treatment. Neuropathic pain induced by peripheral nerve injury is caused, in part, by ectopic discharges from the injury site or the dorsal root ganglia (DRG) resulting in enhanced central input and central hyperexcitability. A heterogeneous family of γ-aminobutyric acid (GABA)(A) channels is important in quieting neuronal excitability. We have recently reported that in vivo modulation of GABAergic neurons in DRG can alter the course of neuropathic pain development after peripheral nerve injury. It seems that direct application of a potent GABA(A) agonist, muscimol, to the ipsilateral DRG prevents the development of hyperalgesia in rats subjected to a sciatic nerve crush injury. In addition to potentially curtailing hyperexcitability, GABAergic stimulation upregulated expression of peripheral myelin protein 22 (PMP22), a key component of the basal lamina. PMP22 expression correlates with peripheral myelin formation and nerve regeneration. Because of the importance of PMP22 for the formation and stability of myelin, and the fact that PMP22 expression could be GABAergically modulated, we examined whether direct DRG application of muscimol can restore PMP22 protein expression and the integrity of nerve fibers after crush injury of a sciatic nerve. Using adult female rats and a crush injury model, we found that GABAergic modulation in the ipsilateral DRG restores PMP22 protein expression in the distal segment of the sciatic nerve and improves myelin stability in the basal membrane of nerve fibers, thus giving the morphological appearance of lessened nerve injury or faster nerve fiber regeneration. Both the enhanced PMP22 protein expression and morphological improvements coincide with the abolishment of thermal and mechanical hypersensitivity. The DRG could be a promising therapeutic target in nerve regeneration and pain alleviation after crush injury of a myelinated peripheral nerve.