Targeting pain-depressed behaviors in preclinical assays of pain and analgesia: Drug effects on acetic acid-depressed locomotor activity in ICR mice

Aims: Pain depresses expression of many behaviors, and one goal of analgesic treatment is to restore pain-depressed behaviors. Assays that focus on pain-depressed behaviors may contribute to preclinical assessment of candidate analgesics. Main methods: This study compared effects of the mu opioid receptor agonist morphine (an acknowledged analgesic), the dopamine receptor antagonist haloperidol (a non-analgesic sedative), the adenosine receptor antagonist caffeine (a non-analgesic stimulant) and the neurokinin-1 receptor antagonist CJ 11.974-01 (a candidate analgesic) on acetic acid-induced writhing (a traditional pain-stimulated behavior) and acetic acid-induced suppression of locomotor activity (a pain-depressed behavior) in male ICR mice. Drug effects on non-depressed (baseline) locomotor activity were also examined. Key findings: I.P. administration of acetic acid (0.18-1%) was equipotent in stimulating writhing and depressing locomotor activity. Morphine blocked both acid-induced stimulation of writhing and depression of locomotion, although it was 56-fold less potent in the assay of acid-depressed locomotion. Haloperidol and CJ 11,974-01 decreased acid-stimulated writhing, but failed to block acid-induced depression of locomotion. Caffeine had no effect on acid-stimulated writhing or acid-depressed locomotor activity, although it did increase non-depressed locomotion. Thus, morphine was the only drug to block both acid-stimulated writhing and acid-depressed locomotion. Significance: Complementary assays of pain-stimulated and pain-depressed behaviors may improve the predictive validity of preclinical studies that assess candidate analgesic drugs. The low potency of morphine to block acid-induced depression of locomotion suggests that locomotor activity may be a relatively insensitive measure for studies of pain-depressed behavior. (C) 2009 Elsevier Inc. All rights reserved.