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Minocycline Prevents Muscular Pain Hypersensitivity and Cutaneous Allodynia Produced by Repeated Intramuscular Injections of Hypertonic Saline in Healthy Human Participants

  • Mohamad Samir Samour
    Correspondence
    Address reprint requests to Mr. Mohamad Samir Samour, Bachelor of Medical Science (Hons), School of Medicine, Western Sydney University, Locked Bag 1797, Penrith, NSW 2751, Australia.
    Affiliations
    Department of Integrative Physiology, School of Medicine, School of Science and Health University of Western Sydney, Penrith, Australia
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  • Saad Saulat Nagi
    Affiliations
    Department of Integrative Physiology, School of Medicine, School of Science and Health University of Western Sydney, Penrith, Australia

    Center for Social and Affective Neuroscience, Linköping University, Linköping, Sweden
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  • Peter John Shortland
    Affiliations
    School of Science and Health, Western Sydney University, Penrith, New South Wales, Australia
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  • David Anthony Mahns
    Affiliations
    Department of Integrative Physiology, School of Medicine, School of Science and Health University of Western Sydney, Penrith, Australia
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      Highlights

      • Repeated injections of hypertonic saline produced a persistent, bilateral muscular hypersensitivity.
      • Cutaneous cold allodynia was also elicited following the repeated injections.
      • The elicited hypersensitivity occurred independently of the acute pain response to hypertonic saline.
      • Minocycline pre-treatment prevented the development of the hypersensitive response.
      • Minocycline did not change any aspect of the acute hypertonic saline pain response

      Abstract

      Minocycline, a glial suppressor, prevents behavioral hypersensitivities in animal models of peripheral nerve injury. However, clinical trials of minocycline in human studies have produced mixed results. This study addressed 2 questions: can repeated injections of hypertonic saline (HS) in humans induce persistent hypersensitivity? Can pretreatment with minocycline, a tetracycline antibiotic with microglial inhibitory effects, prevent the onset of hypersensitivity? Twenty-seven healthy participants took part in this double-blind, placebo-controlled study, consisting of 6 test sessions across 2 weeks. At the beginning of every session, pressure-pain thresholds of the anterior muscle compartment of both legs were measured to determine the region distribution and intensity of muscle soreness. To measure changes in thermal sensitivity in the skin overlying the anterior muscle compartment of both legs, quantitative sensory testing was used to measure the cutaneous thermal thresholds (cold sensation, cold pain, warm sensation, and heat pain) and a mild cooling stimulus was applied to assess the presence of cold allodynia. To induce ongoing hypersensitivity, repeated injections of HS were administered into the right tibialis anterior muscle at 48-hour intervals. In the final 2 sessions (days 9 and 14), only sensory assessments were done to plot the recovery after cessation of HS administrations and drug washout. By day 9, nontreated participants experienced a significant bilateral increase in muscle soreness (P < .0001), accompanied by the emergence of bilateral cold allodynia in 44% of participants, thus confirming the effectiveness of the model. Placebo-treated participants experienced a bilateral 35% alleviation in muscle soreness (P < .0001), with no changes to the prevalence of cold allodynia. In contrast, minocycline-treated participants experienced a bilateral 70% alleviation in muscle soreness (P < .0001), additionally, only 10% of minocycline-treated participants showed cold allodynia. This study showed that repeated injections of HS can induce a hypersensitivity that outlasts the acute response, and the development of this hypersensitivity can be reliably attenuated with minocycline pretreatment.

      Perspective

      Four repeated injections of HS at 48-hour intervals induce a state of persistent hypersensitivity in healthy human participants. This hypersensitivity was characterized by bilateral muscular hyperalgesia and cutaneous cold allodynia, symptoms commonly reported in many chronic pain conditions. Minocycline pretreatment abolished the development of this state.

      Key words

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      1. Shaikh S, Shortland P, Mahns D: Minocycline ameliorates low threshold fibre mediated generalised hypersensitivity following unilateral median nerve injury in rodent glabrous skin. Presented at the 16th World Congress on Pain ,Yokohama, Japan, September 26-30, 2017

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