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

Asiri, Yahya I. BPharm*; Fung, Timothy BSc*; Schwarz, Stephan K. W. MD, PhD, FRCPC*†; Asseri, Khalid A. MSc*; Welch, Ian D. DVM; Schuppli, Catherine A. DVM, PhD‡§; Barr, Alasdair M. PhD*‖; Wall, Richard A. PhD*; Puil, Ernest PhD*; MacLeod, Bernard A. MD, FRCPC*

doi: 10.1213/ANE.0000000000002525
Research Report: PDF Only

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 ( 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 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, 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 coinjections of lidocaine (0.003%–1%) with 10% HS. Histopathologic assessment revealed no tissue damage due to HS.

CONCLUSIONS: The 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.

From the *Hugill Anesthesia Research Centre, Department of Anesthesiology, Pharmacology & Therapeutics, the University of British Columbia, Vancouver, British Columbia, Canada; Department of Anesthesia, St Paul’s Hospital/Providence Health Care, Vancouver, British Columbia, Canada; Department of Animal Care Services, the University of British Columbia, Vancouver, British Columbia, Canada; §Faculty of Land and Food Systems, the University of British Columbia, Vancouver, British Columbia, Canada; and BC Children’s Hospital Research Institute, the University of British Columbia, Vancouver, British Columbia, Canada.

Accepted for publication August 24, 2017.

Funding: This work was funded in part by the Dr Jean Templeton Hugill Endowment for Anesthesia Memorial Fund and The University of British Columbia Faculty of Medicine. S.K.W.S. holds the Dr Jean Templeton Hugill Chair in Anesthesia.

Conflicts of Interest: See Disclosures at the end of the article.

Reprints will not be available from the authors.

Address correspondence to Bernard A. MacLeod, MD, FRCPC, Department of Anesthesiology, Pharmacology & Therapeutics, The University of British Columbia, 2176 Health Sciences Mall, Vancouver, BC, Canada V6T 1Z3. Address e-mail to

© 2018 International Anesthesia Research Society
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