Although it is generally accepted that after nerve injury, nociceptors and their central relay neurons undergo neuroplastic adaptations and these changes can significantly affect chronic pain status, knowledge regarding the transcription program that regulates the plasticity of nociceptors after nerve injury is currently lacking. We recently reported that the transcription factor Soxl 1 regulates the survival and axonal growth of embryonic sensory neurons including nociceptors. Soxl 1 is one of the few transcription factors whose expression is significantly upregulated in sensory neurons after nerve injury. We hypothesize that the upregulation of Sox11 after nerve injury is an adaptive change on the part of the nervous system to promote homeostasis and reinnervation of distal territories, protecting against the development of neuropathic pain. Alternatively, the upregulation of Soxl 1 after nerve injury may lead to transcriptional changes in nociceptive neurons that alter their threshold, excitability and transmission properties and contribute to pain hypersensitivity. In this proposal, we will use newly developed nociceptor-specific Soxli CKO mice to directly test our hypotheses. We have three specific aims: 1) Examine the role of Soxl 1 in regulating latestage nociceptor development including survival, axonal growth and target innervation, and expression of nociceptor-specific ion channels and receptors;2) Determine whether the upregulation of Soxl 1 promotes or inhibits the development of behavioral hypersensitivity after peripheral nerve injury. We will compare the behavioral responses of Soxl 1 CKO mice and control littermates to mechanical and thermal stimuli after two types of nerve injuries, sciatic nerve crush which allows for reinnervation of distal territories, and L5 spinal nerve transection which does not allow for reinnervation;and 3) Assess the role of Soxl 1 in axonal growth and target reinnervation after peripheral nerve injury. The long-term goal of our study is to understand the molecular mechanisms that regulate the plasticity of nociceptors after nerve injury in order to identify novel therapeutic targets for prevention and management of chronic pain.
Neuropathic pain is a particularly debilitating form of chronic pain and current therapeutic options are limited in terms of efficacy and/or side effects. Elucidating the mechanisms regulating the plasticity of nociceptors after nerve injury is of fundamental importance and will identify novel therapeutic targets for prevention or management of chronic pain.
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