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. 2023 Oct 11;4:1281698. doi: 10.3389/fpain.2023.1281698

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© 2023 Negus, Akbarali, Kang, Lee, Marsh, Santos and Zhang.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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Schematic illustration of drug effects in preclinical assays of pain-depressed behavior. In assays of pain-depressed behavior, the noxious stimulus decreases expression of the measured behavior from high baseline levels (open circle over “BL”) to low levels in the pain state (filled circle over “Pain”). In the present study, IP acid served as the noxious stimulus to decrease crosses and movement counts as measures of locomotor behavior. Drugs can produce analgesic effects that block effects of the noxious stimulus and increase behavior (green dotted line) and/or motor impairment effects that decrease behavior (red dashed line), and these effects are integrated to produce a net change in expression of the pain-depressed behavior (blue solid line). When a drug produces analgesia without motor impairment, then the drug dose-dependently restores behavior back to baseline levels (left panel; e.g. ketoprofen in the present study). When a drug produces both analgesia and motor impairment, then net effects will depend on the degree of separation between analgesic and motor impairing effects, and motor impairment may constrain analgesia-induced restoration of pain-depressed behavior (center panel; e.g. many MOR agonists in the present study). Lastly, if a drug produces no analgesia but does produce motor impairment, then the drug will fail to restore pain-depressed behavior and may exacerbate pain-related behavioral depression (right panel; e.g. diazepam in the present study).