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Plasma Membrane Mechanisms in a Preclinical Rat Model of Chronic Pain

  • Luiz F. Ferrari
    Affiliations
    Departments of Medicine and Oral Surgery, and Division of Neuroscience, University of California at San Francisco, San Francisco, California
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  • Jon D. Levine
    Correspondence
    Address reprint requests to Jon D. Levine, MD, PhD, University of California, San Francisco, 521 Parnassus Avenue, San Francisco, CA 94143-0440.
    Affiliations
    Departments of Medicine and Oral Surgery, and Division of Neuroscience, University of California at San Francisco, San Francisco, California
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Published:November 04, 2014DOI:https://doi.org/10.1016/j.jpain.2014.10.007

      Highlights

      • Integrin β1 transduces signals from extracellular matrix in a model of chronic pain.
      • Membrane lipid rafts also contribute to mechanisms of hyperalgesia in a model of chronic pain.
      • Our findings help define plasma membrane mechanisms in a preclinical model of chronic pain.

      Abstract

      We have recently shown that the prolongation of prostaglandin E2 hyperalgesia in a preclinical model of chronic pain—hyperalgesic priming—is mediated by release of cyclic adenosine monophosphate from isolectin B4–positive nociceptors and its metabolism by ectonucleotidases to produce adenosine. The adenosine, in turn, acts in an autocrine mechanism at an A1 adenosine receptor whose downstream signaling mechanisms in the nociceptor are altered to produce nociceptor sensitization. We previously showed that antisense against an extracellular matrix molecule, versican, which defines the population of nociceptors involved in hyperalgesic priming, eliminated the prolongation of prostaglandin E2 hyperalgesia. To further evaluate the mechanisms at the interface between the extracellular matrix and the nociceptor's plasma membrane involved in hyperalgesia prolongation, we interrupted a plasma membrane molecule involved in versican signaling, integrin β1, with an antisense oligodeoxynucleotide. Integrin β1 antisense eliminated mechanical hyperalgesia induced by an adenosine A1 receptor agonist, cyclopentyladenosine, in the primed rat. We also disrupted a molecular complex of signaling molecules that contains integrin β1, lipid rafts, with methyl-β-cyclodextrin, which attenuated the prolongation without affecting the acute phase of prostaglandin E2 hyperalgesia, while having no effect on cyclopentyladenosine hyperalgesia. Our findings help to define the plasma membrane mechanisms involved in a preclinical model of chronic pain.

      Perspective

      The present study contributes to a further understanding of mechanisms involved in the organization of messengers at the plasma membrane that participate in the transition from acute to chronic pain.

      Key words

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