DEVELOPMENT AND VALIDATION OF A TOPICAL CAPSAICIN-INDUCED THERMAL AND COLD SENSITIZATION MODEL IN RHESUS MONKEYS WITH ORAL GABAPENTIN AND IT SIRNA TARGETING NAV1.7 INTERVENTION

Preclinical models using NHPs offer valuable translational insights for pain research. In this study, we developed and validated a conscious rhesus model to assess tail-withdrawal reflexes in response to thermal and cold stimuli and explored pharmacologic modulation using oral gabapentin and intrathecal (IT) lipid-conjugated siRNA silencing Nav1.7. Tail reflexes were measured in awake rhesus restrained in a primate chair. Tails were immersed in water at three temperatures: non-noxious cold (2°C) and warm (42°C), and acutely noxious heat (55°C). Tail-withdrawal latency was recorded under each condition. A capsaicin-based model was used to induce both cold and thermal sensitization. Gabapentin was administered orally, and its analgesic effects were evaluated in both the 55°C and the capsaicin-induced sensitization models at 42°C. Spinal cord, DRG and other brain tissues were collected in the end of the study. Prior to capsaicin application, tails remained immersed for the full 20 seconds in the non-noxious conditions. Withdrawal latencies were significantly reduced to <5 seconds in the noxious condition, or following induction of sensitization in non-noxious conditions. Oral gabapentin temporarily reversed thermal sensitization. IT administration of siRNA resulted in approximately 50% SCN9A mRNA reduction in the dorsal root ganglion, and spinal cord within two weeks which resulted in persistent reverse themal sensitization. This study establishes a robust and reproducible conscious rhesus model for evaluating both thermal and cold sensitization. Capsaicin sensitization effectively models neuropathic pain states, while systemic and intrathecal drug delivery routes enable translationally relevant pain modulation studies.