Silencing Nociceptors Using DREADDs to Improve Functional Outcomes after Spinal Cord Injury
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A new chemogenetic treatment for inhibition of pain signaling in the peripheral nervous system will be tested using a spinal cord injury model. More than half of spinal cord injury patients experience chronic neuropathic pain that is refractory to treatment. This pain is thought to arise after spinal cord injury due to the uncontrolled signaling of nociceptors, a class of peripheral sensory neurons that send pain signals to the central nervous system. Previous research has shown that hyperactivity of nociceptors in the acute phase of injury can prevent long term motor recovery and lead to chronic pain. The goal of this study is to silence these miscommunicating pain neurons using viral vector (AAV6)-mediated gene delivery to nociceptors. We used this approach to deliver a gene encoding a designer receptor exclusively activated by designer drugs (Gi-DREADD). This receptor silences neuron activity when bound to an inert ligand that is injected into the rat. This virus has been reported to be highly selective for nociceptors in mice by another group. However, the virus has not previously been tested in a spinal cord injury model. We have performed three studies to determine: (1) the selectivity of AAV6-mediated gene therapy to transduce peripheral nociceptors with Gi-DREADD, (2) the efficiency of gene delivery using different injection techniques, and (3) the subpopulations of nociceptors that are transduced using this approach. We have identified optimized viral vector delivery strategies that yield transduction in more than 20% of nociceptors. Additionally, we have observed that AAV6 is highly selective for nociceptors in rats, exhibiting >99% specificity for small-diameter pain neurons including multiple molecularly distinct subtypes of nociceptors. Finally, in a pilot behavioral study we found a strong and significant correlation between the proportions of DREADD-expressing nociceptors and inhibition of thermal pain responses. Future work will use our optimized gene delivery strategy to test whether nociceptor silencing with DREADDs is sufficient to prevent long-term neurological deficits after spinal cord injury. We predict that silencing nociceptors early after spinal cord injury in rats will reduce long-term pain outcomes and lead to functional recovery.
SubjectSCI, pain, DREADD, nociceptor
Adkins, Robert Lewis (2019). Silencing Nociceptors Using DREADDs to Improve Functional Outcomes after Spinal Cord Injury. Undergraduate Research Scholars Program. Available electronically from