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.
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.
|Ferrari, L F; Araldi, D; Bogen, O et al. (2016) Extracellular matrix hyaluronan signals via its CD44 receptor in the increased responsiveness to mechanical stimulation. Neuroscience 324:390-8|
|Araldi, Dioneia; Ferrari, Luiz F; Levine, Jon D (2016) Adenosine-A1 receptor agonist induced hyperalgesic priming type II. Pain 157:698-709|
|Ferrari, Luiz F; Khomula, Eugen V; Araldi, DionÃ©ia et al. (2016) Marked Sexual Dimorphism in the Role of the Ryanodine Receptor in a Model of Pain Chronification in the Rat. Sci Rep 6:31221|
|Araldi, Dioneia; Ferrari, Luiz F; Levine, Jon D (2016) Gi-protein-coupled 5-HT1B/D receptor agonist sumatriptan induces type I hyperalgesic priming. Pain 157:1773-82|
|Bogen, Oliver; Bender, Olaf; LÃ¶we, Jana et al. (2015) Neuronally produced versican V2 renders C-fiber nociceptors IB4 -positive. J Neurochem 134:147-55|
|Ferrari, Luiz F; Bogen, Oliver; Reichling, David B et al. (2015) Accounting for the delay in the transition from acute to chronic pain: axonal and nuclear mechanisms. J Neurosci 35:495-507|
|Ferrari, Luiz F; Levine, Jon D (2015) Plasma membrane mechanisms in a preclinical rat model of chronic pain. J Pain 16:60-6|
|Ferrari, Luiz F; Araldi, Dioneia; Levine, Jon D (2015) Distinct terminal and cell body mechanisms in the nociceptor mediate hyperalgesic priming. J Neurosci 35:6107-16|
|Araldi, Dioneia; Ferrari, Luiz F; Levine, Jon D (2015) Repeated Mu-Opioid Exposure Induces a Novel Form of the Hyperalgesic Priming Model for Transition to Chronic Pain. J Neurosci 35:12502-17|
|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|
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