CaMKIIα-NpHR-Mediated Optogenetic Inhibition of DRG Glutamatergic Neurons by Flexible Optic Fiber Alleviates Chronic Neuropathic Pain.

Abstract

Glutamatergic neurons of the dorsal root ganglion (DRGg) exert a significant effect on peripheral nociceptive signal transmission. However, assessing the explicit modulatory effect of DRGg during chronic neuropathic pain (CNP) with neuromodulation techniques remains largely unexplored. Therefore, we inhibited DRGg by optogenetic stimulation and examined whether it could alleviate CNP and associated anxiety-related behaviors in a chronic compressed DRG (CCD) rat model. The CCD pain model was established by inserting an L-shaped rod into the lumbar 5 (L5) intervertebral foramen, and either AAV2-CaMKIIα-eNpHR3.0-mCherry or AAV2-CaMKIIα-mCherry was injected into the L5 DRG. Flexible optic fibers were implanted to direct yellow light into the L5 DRG. Pain and anxiety-related behavioral responses were assessed using mechanical threshold, mechanical latency, thermal latency, and open field tests. In vivo single-unit extracellular recording from the DRG and ventral posterolateral (VPL) thalamus was performed. CNP and anxiety-related behavioral responses along with increased neural firing activity of the DRG and VPL thalamus were observed in CCD animals. Enhanced expression of nociception-influencing molecules was found in the DRG and spinal dorsal horn (SDH). In contrast during optogenetic stimulation, specific DRGg inhibition markedly alleviated the CNP responses and reduced the DRG and VPL thalamic neural hyperactivity in CCD animals. Inhibition of DRGg also reduced the active expression of nociceptive signal mediators in the DRG and SDH. Taken together, our findings suggest that CaMKIIα-NpHR-mediated optogenetic inhibition of DRGg can produce antinociceptive effects in CCD rats during peripheral nerve injury-induced CNP condition by altering peripheral nociceptive signal input in the spinothalamic tract.