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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Exploratory Grants (P20)
Project #
5P20GM103643-02
Application #
8529582
Study Section
Special Emphasis Panel (ZRR1-RI-4)
Project Start
Project End
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
2
Fiscal Year
2013
Total Cost
$220,674
Indirect Cost
$52,172
Name
University of New England
Department
Type
DUNS #
071735252
City
Biddeford
State
ME
Country
United States
Zip Code
04005
Govea, Rosann M; Barbe, Mary F; Bove, Geoffrey M (2017) Group IV nociceptors develop axonal chemical sensitivity during neuritis and following treatment of the sciatic nerve with vinblastine. J Neurophysiol 118:2103-2109
Lei, Wei; Mullen, Nathan; McCarthy, Sarah et al. (2017) Heat-shock protein 90 (Hsp90) promotes opioid-induced anti-nociception by an ERK mitogen-activated protein kinase (MAPK) mechanism in mouse brain. J Biol Chem 292:10414-10428
Havelin, Joshua; Imbert, Ian; Sukhtankar, Devki et al. (2017) Mediation of Movement-Induced Breakthrough Cancer Pain by IB4-Binding Nociceptors in Rats. J Neurosci 37:5111-5122
Follansbee, Taylor L; Gjelsvik, Kayla J; Brann, Courtney L et al. (2017) Drosophila Nociceptive Sensitization Requires BMP Signaling via the Canonical SMAD Pathway. J Neurosci 37:8524-8533
Cormier, Jim; Cone, Katherine; Lanpher, Janell et al. (2017) Exercise reverses pain-related weight asymmetry and differentially modulates trabecular bone microarchitecture in a rat model of osteoarthritis. Life Sci 180:51-59
Allen, Joshua; Imbert, Ian; Havelin, Joshua et al. (2017) Effects of Treadmill Exercise on Advanced Osteoarthritis Pain in Rats. Arthritis Rheumatol 69:1407-1417
McLane, Virginia D; Bergquist, Ivy; Cormier, James et al. (2017) Long-term morphine delivery via slow release morphine pellets or osmotic pumps: Plasma concentration, analgesia, and naloxone-precipitated withdrawal. Life Sci 185:1-7
Harasawa, Ichiro; Johansen, Joshua P; Fields, Howard L et al. (2016) Alterations in the rostral ventromedial medulla after the selective ablation of ?-opioid receptor expressing neurons. Pain 157:166-73
Havelin, Joshua; Imbert, Ian; Cormier, Jennifer et al. (2016) Central Sensitization and Neuropathic Features of Ongoing Pain in a Rat Model of Advanced Osteoarthritis. J Pain 17:374-82
Malon, Jennifer T; Cao, Ling (2016) Preparation of Primary Mixed Glial Cultures from Adult Mouse Spinal Cord Tissue. J Vis Exp :

Showing the most recent 10 out of 30 publications