An Intraplantar Hypertonic Saline Assay in Mice for Rapid Screening of Analgesics

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Abstract

BACKGROUND:

Development of new analgesics is limited by shortcomings of existing preclinical screening assays such as wide variations in response, suitability for a narrow range of analgesics, and propensity to induce tissue damage. Our aim was to determine the feasibility of a new in vivo animal assay as an analgesic screen based on nociceptive responses (licking and biting) after intraplantar (i.pl.) injection of hypertonic saline (HS) in mice.

METHODS:

With approval from the Institutional Animal Care Committee, we conducted a randomized, investigator-blinded in vivo study in adult CD-1 mice. We first studied the concentration–response relationship, time course, and sex difference of animals’ nociceptive responses to HS. Subsequently, we assessed the screening ability of the HS assay to detect a range of established analgesics belonging to different classes. Finally, we performed histopathologic studies to assess potential tissue damage.

RESULTS:

The response produced by i.pl. HS was greater and longer in female than in male mice. The responses to HS were concentration dependent with minimal variance. Ten percent HS evoked a maximal response within the first 5 minutes. Morphine dose-dependently attenuated animals’ nociceptive responses (1–10 mg/kg intraperitoneally [i.p.]). The peripherally restricted µ-opioid receptor agonist, loperamide, reduced nociceptive responses when injected locally (30–100 µg/paw, i.pl.) but not systemically (1–10 mg/kg, i.p.). Acetylsalicylic acid (300 mg/kg, i.p.), naproxen (150 mg/kg, i.p), and acetaminophen (300 mg/kg, i.p.) all decreased nociceptive responses, as did i.pl. coinjections of lidocaine (0.003%–1%) with 10% HS. Histopathologic assessment revealed no tissue damage due to HS.

CONCLUSIONS:

The i.pl. HS assay is easily performed, rapidly detects standard analgesics, and produces minimal animal suffering without tissue damage. We propose this assay as a useful addition to the armamentarium of existing preclinical analgesic screens.

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