Pain stimulates some behaviors (e.g., withdrawal responses) and depresses other behaviors (e.g., feeding, locomotion). We are developing methods for testing candidate analgesics using measurements of pain-depressed behaviors. Such assays may model important aspects of clinical pain and complement traditional procedures that measure pain-stimulated behaviors. The present study characterized the effects of a chronic pain manipulation (monosodium iodoacetate (MIA)-induced osteoarthritis) on wheel running in rats. Rats had 24hr voluntary access to running wheels. Duration of running wheel acquisition was manipulated such that rats had either 21 or 7 days of running wheel access prior to MIA administration. Wheel running was monitored for an additional 21 days following MIA administration. MIA produced concentration-and acquisition lengthdependent decreases in wheel running. Parallel experiments demonstrated that MIA produced concentration-dependent tactile allodynia and shifts in hind limb weight bearing. MIA was differentially potent across assays with a potency rank: weight-bearing ≥ von Frey > running wheel. MIA produced greater depression of wheel running in rats with relatively high baseline running rates compared to rats with relatively low baseline running rates. The differential potency of MIA across assays and apparent rate-dependent effects in running wheels may impact our traditional interpretations of preclinical nociceptive and antinociceptive testing.

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 painstimulated 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 aciddepressed 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. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. 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. Significance-Complementary NIH Public Access

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Opioid analgesics remain a mainstay for the treatment of acute and chronic pain. The use of these agents is associated with significant side effects including addiction and gastrointestinal (GI) dysfunction. Our laboratory has previously reported on the in vivo pharmacology of 6ß‐naltrexol, an active metabolite of naltrexone and a putative neutral antagonist. The current studies assessed the in vivo pharmacology of a related compound, 6ß‐naltrexamine, which also acts as a neutral antagonist in opioid‐exposed cell systems. I.v. administration of 6ß‐naltrexamine, in male ICR mice, resulted in a time related blockade of the antinociceptive effects of i.v. hydrocodone, ID50 value (95% CI) of 2.03 (1.68–2.46) mg/kg. The antagonist had a peak effect at 60 minutes and duration of action of approximately 90 minutes in the 55°C tail‐flick test. 6ß‐naltrexamine also dose‐dependently reversed hydrocodone‐induced GI inhibition with an ID50 value (95% CI) of 4.14 (2.23–7.71) mg/kg. These results indicated that 6ß‐naltrexamine is a relatively potent opioid antagonist that exhibits a CNS/PNS potency ratio similar to naltrexone and naloxone. We are currently assessing the efficacy of 6ß‐naltrexamine in animal models of acute and chronic dependence.

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