Nerve injury-induced neuropathic pain following surgery or trauma has a significant economic burden that impairs quality of life. Despite the identification of a host of molecular targets implicated in the development of neuropathic pain, post-surgical and post-trauma neuropathic pains are often intractable. Unlike other neuropathic pain conditions, such as diabetic neuropathy, the time that nerve injury occurs during surgery or following trauma is well defined. As a result, it is possible that a pre-emptive intervention, either during the perioperative period or shortly after the trauma, could prevent the development of persistent pain. Indeed, local anesthetic based pre-emptive analgesia techniques have been developed. However, although these techniques are very good in managing immediate post-surgical pain, they only offer limited long-term benefit. In a mouse model of neuropathic pain in which the sciatic nerve is surgically injured, we recently demonstrated a critical contribution of injury-induced de novo synthesis and release of the cytokine, colony stimulating factor 1 (CSF1, also known as macrophage colony stimulating factor) from dorsal root ganglion (DRG) sensory neurons. Our studies established that CSF1 is both necessary and sufficient for nerve injury-induced activation of spinal cord microglia, the tissue macrophages of the CNS, and for post-injury mechanical hypersensitivity/ neuropathic pain behavior. Here, in Specific Aims 1 and 2, we propose experiments that will first define the transcriptional mechanism that triggers CSF1 induction in injured DRG neurons. Our preliminary analysis of the Santa Cruz Genome Browser ChIP-Seq data from B-cell lymphoma revealed 19 transcription factors that bind to CSF1 promoter. Among these 19 genes, using quantitative RT-PCR we determined that c-Myc is also induced in DRG after nerve injury. Interestingly, the c-Myc induction occurred within hours of nerve injury, well before the induction of CSF1. Immunohistochemistry confirmed the induction of c-Myc and its co-expression with CSF1 in DRG neurons. Of note, c-Myc is a universal amplifier of gene expression in cancer and embryonic development, but its function in adult non-proliferating cells is largely unknown. More importantly, pre-emptive local anesthetic treatment of sciatic nerve prior to the injury did not prevent the induction of c-Myc in DRG neurons, indicating that its induction is not activity dependent. Based on these findings, we hypothesize that c-Myc is a major contributor to CSF1 gene induction in the injured DRG neurons, and that targeting c-Myc might prevent the CSF1 gene induction and thus prevent neuropathic pain development. Finally, as the expression of CSF1 persists for weeks after nerve injury, we will also test the hypothesis that CSF1 not only contributes to the initiation of the neuropathic pain phenotype, but also to its persistence. Thus in Specific Aim 3, we will delete or block CSF1 from DRG neurons after injury occurs. Finally, given recent evidence for differences in microglial contribution to the neuropathic pain phenotype in male and female mice, our studies will also assess the contribution of these mechanisms both in male and female mice.

Public Health Relevance

This proposal examines key biochemical processes in sensory neurons that contribute to nerve injury-induced neuropathic pain. We propose experiments to define the transcriptional mechanisms that trigger induction of a gene (CSF1) that we previously implicated in the neuropathic pain process. We hypothesize that targeting this transcriptional mechanism may prevent persistent postoperative pain and could reverse the neuropathic pain that often develops after traumatic nerve injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS100801-04
Application #
9994390
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Oshinsky, Michael L
Project Start
2017-07-01
Project End
2022-06-30
Budget Start
2020-07-01
Budget End
2021-06-30
Support Year
4
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94118
Zhou, Wei; Cheung, Kevin; Kyu, Steven et al. (2018) Activation of orexin system facilitates anesthesia emergence and pain control. Proc Natl Acad Sci U S A 115:E10740-E10747