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Topical Combinations Aimed at Treating Microvascular Dysfunction Reduce Allodynia in Rat Models of CRPS-I and Neuropathic Pain

  • J. Vaigunda Ragavendran
    Affiliations
    Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, Canada

    Department of Anesthesia, McGill University, Montreal, QC, Canada
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  • André Laferrière
    Affiliations
    Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, Canada

    Department of Anesthesia, McGill University, Montreal, QC, Canada
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  • Wen Hua Xiao
    Affiliations
    Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, Canada

    Department of Anesthesia, McGill University, Montreal, QC, Canada

    Faculty of Dentistry, McGill University, Montreal, QC, Canada
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  • Gary J. Bennett
    Affiliations
    Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, Canada

    Department of Anesthesia, McGill University, Montreal, QC, Canada

    Faculty of Dentistry, McGill University, Montreal, QC, Canada
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  • Satyanarayana S.V. Padi
    Affiliations
    Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, Canada

    Faculty of Dentistry, McGill University, Montreal, QC, Canada
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  • Ji Zhang
    Affiliations
    Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, Canada

    Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada

    Faculty of Dentistry, McGill University, Montreal, QC, Canada
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  • Terence J. Coderre
    Correspondence
    Address reprint requests to Terence J. Coderre, Anesthesia Research Unit, McGill University, 3655 Promenade Sir William Osler, Montreal, QC, H3G 1Y6, Canada.
    Affiliations
    Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, Canada

    Department of Anesthesia, McGill University, Montreal, QC, Canada

    Department of Psychology, McGill University Health Centre Research Institute, McGill University, Montreal, QC, Canada

    Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada
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      Abstract

      Growing evidence indicates that various chronic pain syndromes exhibit tissue abnormalities caused by microvasculature dysfunction in the blood vessels of skin, muscle, or nerve. We tested whether topical combinations aimed at improving microvascular function would relieve allodynia in animal models of complex regional pain syndrome type I (CRPS-I) and neuropathic pain. We hypothesized that topical administration of either α2-adrenergic (α2A) receptor agonists or nitric oxide (NO) donors combined with either phosphodiesterase (PDE) or phosphatidic acid (PA) inhibitors would effectively reduce allodynia in these animal models of chronic pain. Single topical agents produced significant dose-dependent antiallodynic effects in rats with chronic postischemia pain, and the antiallodynic dose-response curves of PDE and PA inhibitors were shifted 2.5- to 10-fold leftward when combined with nonanalgesic doses of α2A receptor agonists or NO donors. Topical combinations also produced significant antiallodynic effects in rats with sciatic nerve injury, painful diabetic neuropathy, and chemotherapy-induced painful neuropathy. These effects were shown to be produced by a local action, lasted up to 6 hours after acute treatment, and did not produce tolerance over 15 days of chronic daily dosing. The present results support the hypothesis that allodynia in animal models of CRPS-I and neuropathic pain is effectively relieved by topical combinations of α2A or NO donors with PDE or PA inhibitors. This suggests that topical treatments aimed at improving microvascular function may reduce allodynia in patients with CRPS-I and neuropathic pain.

      Perspective

      This article presents the synergistic antiallodynic effects of combinations of α2A or NO donors with PDE or PA inhibitors in animal models of CRPS-I and neuropathic pain. The data suggest that effective clinical treatment of chronic neuropathic pain may be achieved by therapies that alleviate microvascular dysfunction in affected areas.

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