The concept of a transition from acute to chronic pain that recognizes the difficulty to reverse plasticity in pain mechanisms, has provided the impetus for the development of preclinical models to evaluate neuroplasticity in elements of pain circuits, including in the primary afferent nociceptor. We propose to test the hypothesis that neuroplastic changes in a model of the transition from acute to chronic pain, hyperalgesic priming, involves translation of new protein from dormant mRNA in the peripheral terminal of the nociceptor. Importantly, in preliminary studies we have found that translation inhibitors are able to reverse the neuroplastic changes underlying hyperalgesic priming. To investigate this mechanism, we will evaluate whether cytoplasmic polyadenylation element binding protein (CPEB), a regulator of protein translation in axons that has been implicated in neuroplasticity, orchestrates the effects of protein kinase C? (PKC?) on a downstream protein, calcium-calmodulin kinase II (CaMKII), and the ryanodine receptor activation of which releases Ca2+ which can activate CaMKII, which has been implicated in neuroplasticity in high threshold Aplysia sensory neurons. Importantly the proposed experiments will distinguish between the peripheral protein translation dependent neuroplastic changes, and how it might be reversed. Finally, we also propose to investigate the hypothesis that a cAMP-dependent autocrine mechanism of hyperalgesia is upstream of PKC? in the expression of the prolongation of hyperalgesia characteristic of the primed nociceptor, and also identify the second messengers that are downstream of PKC?. The results of these studies could guide the rational design of entirely new classes of therapeutic agents for the treatment of chronic pain syndromes, and the signaling pathways downstream of PKC? that mediate the prolonged hyperalgesia.

Public Health Relevance

Determining the cellular mechanisms that maintain the chronic pain state and identifying the limited subpopulation of nerve fibers in which these mechanisms occur would provide a framework for understanding the difficulties clinicians experience in treating many patients with chronic pain syndromes, and suggest a new approach for the development of novel classes of drugs to treat the basic mechanisms that underlie chronic pain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS084545-05
Application #
9464574
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Oshinsky, Michael L
Project Start
2014-04-01
Project End
2019-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
5
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Dentistry
Type
Schools of Dentistry/Oral Hygn
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94118
Araldi, Dioneia; Khomula, Eugen V; Ferrari, Luiz F et al. (2018) Fentanyl Induces Rapid Onset Hyperalgesic Priming: Type I at Peripheral and Type II at Central Nociceptor Terminals. J Neurosci 38:2226-2245
Ferrari, Luiz F; Khomula, Eugen V; Araldi, Dioneia et al. (2018) CD44 Signaling Mediates High Molecular Weight Hyaluronan-Induced Antihyperalgesia. J Neurosci 38:308-321
Sung, Kijung; Ferrari, Luiz F; Yang, Wanlin et al. (2018) Swedish Nerve Growth Factor Mutation (NGFR100W) Defines a Role for TrkA and p75NTR in Nociception. J Neurosci 38:3394-3413
Araldi, Dionéia; Ferrari, Luiz F; Levine, Jon D (2018) Mu-opioid Receptor (MOR) Biased Agonists Induce Biphasic Dose-dependent Hyperalgesia and Analgesia, and Hyperalgesic Priming in the Rat. Neuroscience 394:60-71
Araldi, Dionéia; Ferrari, Luiz F; Levine, Jon D (2018) Role of GPCR (mu-opioid)-receptor tyrosine kinase (epidermal growth factor) crosstalk in opioid-induced hyperalgesic priming (type II). Pain 159:864-875
Ferrari, Luiz F; Araldi, Dioneia; Green, Paul et al. (2018) Age-Dependent Sexual Dimorphism in Susceptibility to Develop Chronic Pain in the Rat. Neuroscience 387:170-177
Araldi, Dioneia; Ferrari, Luiz F; Levine, Jon D (2017) Hyperalgesic priming (type II) induced by repeated opioid exposure: maintenance mechanisms. Pain 158:1204-1216
Araldi, Dioneia; Ferrari, Luiz F; Green, Paul et al. (2017) Marked sexual dimorphism in 5-HT1 receptors mediating pronociceptive effects of sumatriptan. Neuroscience 344:394-405
Ferrari, Luiz F; Araldi, Dionéia; Levine, Jon D (2017) Regulation of Expression of Hyperalgesic Priming by Estrogen Receptor ? in the Rat. J Pain 18:574-582
Khomula, Eugen V; Ferrari, Luiz F; Araldi, Dionéia et al. (2017) Sexual Dimorphism in a Reciprocal Interaction of Ryanodine and IP3 Receptors in the Induction of Hyperalgesic Priming. J Neurosci 37:2032-2044

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