Musculoskeletal pain is the most frequent and expensive condition for worker compensation and disability. Previous investigations into the pathogenesis of work- related musculoskeletal pain have tended to focus on the possibility of pathology in muscle cells;however, it is clear that chronic ergonomic muscle pain can occur without any signs of cellular injury in the muscle. During the current funding period we have provided extensive evidence, in two animal models of ergonomic muscle pain (vibration and eccentric exercise) that the muscle nociceptor is a primary locus of pathophysiological changes that produce chronic muscle pain. Furthermore, these models exhibit a neuroplastic shift from acute hyperalgesia to chronic hyperalgesic priming that enables us to study the cellular mechanisms of the transition from acute to chronic muscle pain. Based on those findings, this proposal outlines a project that will employ two innovative approaches to advance our understanding of the underlying cellular mechanisms of chronic muscle pain. First, we will pursue our preliminary observations which suggest a discrete subpopulation of nociceptors plays a critical role in chronic ergonomic muscle pain, and that distinctive features of this subpopulation (sensitivity to GDNF and versican-dependent binding of IB4) are not just convenient markers to distinguish them from other subpopulations, but in fact, play a crucial role in their unique contribution to chronic muscle pain. Second, in view of the prominent clinical role stress plays in the pathophysiology of chronic muscle pain syndromes, we will investigate the nociceptor as a primary site at which activation of neuroendocrine stress axes contributes to chronic pain. The multi-disciplinary expertise of the PI's laboratory enables this proposal to outline a research plan based on the concerted use of behavioral, pharmacological, anatomical, and in vivo electrophysiological and in vitro neurophysiological methods.

Public Health Relevance

Work-related musculoskeletal pain can transition from acute to chronic, especially in the presence of stress, becoming intractable to currently available therapies. The major obstacle to the development of new therapies is our poor understanding of the underlying cellular mechanisms. By studying mechanisms in a discrete subpopulation of nociceptors crucial to its pathophysiology of chronic muscle pain, this work could provide a foundation for the development of new approaches in the treatment of chronic intractable ergonomic muscle pain.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-IFCN-B (03))
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Nuckolls, Glen H
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University of California San Francisco
Schools of Dentistry
San Francisco
United States
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Alvarez, Pedro; Green, Paul G; Levine, Jon D (2018) Neonatal Handling Produces Sex Hormone-Dependent Resilience to Stress-Induced Muscle Hyperalgesia in Rats. J Pain 19:670-677
Alvarez, Pedro; Bogen, Oliver; Green, Paul G et al. (2017) Nociceptor interleukin 10 receptor 1 is critical for muscle analgesia induced by repeated bouts of eccentric exercise in the rat. Pain 158:1481-1488
Conner, Lindsay B; Alvarez, Pedro; Bogen, Oliver et al. (2016) Role of Kv4.3 in Vibration-Induced Muscle Pain in the Rat. J Pain 17:444-50
Bogen, Oliver; Bender, Olaf; Löwe, Jana et al. (2015) Neuronally produced versican V2 renders C-fiber nociceptors IB4 -positive. J Neurochem 134:147-55
Alvarez, P; Levine, J D (2015) Antihyperalgesic effect of tetrodotoxin in rat models of persistent muscle pain. Neuroscience 311:499-507
Alvarez, Pedro; Levine, Jon D; Green, Paul G (2015) Neonatal handling (resilience) attenuates water-avoidance stress induced enhancement of chronic mechanical hyperalgesia in the rat. Neurosci Lett 591:207-11
Alvarez, P; Giudice, L C; Levine, J D (2015) Impact of surgical excision of lesions on pain in a rat model of endometriosis. Eur J Pain 19:103-10
Joseph, Elizabeth K; Green, Paul G; Levine, Jon D (2014) ATP release mechanisms of endothelial cell-mediated stimulus-dependent hyperalgesia. J Pain 15:771-7
Alvarez, Pedro; Bogen, Oliver; Levine, Jon D (2014) Role of nociceptor estrogen receptor GPR30 in a rat model of endometriosis pain. Pain 155:2680-6
Alvarez, P; Bogen, O; Chen, X et al. (2014) Ectopic endometrium-derived leptin produces estrogen-dependent chronic pain in a rat model of endometriosis. Neuroscience 258:111-20

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