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
Previous work in our laboratories provides preclinical evidence that mixed-action delta/mu receptor glycopeptides have equivalent efficacy for treating pain with reduced side effect profiles compared to widely used mu agonist analgesics such as morphine. This study evaluated the rewarding and reinforcing effects of a lead candidate, mixed-action delta/mu agonist MMP-2200, using a conditioned place preference assay as well as a drug self-administration procedure in rats. In place conditioning studies, rats underwent a 2-week conditioning protocol and were then tested for chamber preference. Rats receiving MMP-2200, at previously determined analgesic doses, could not distinguish between the drug and saline-paired chamber, whereas rats receiving the opioid agonist morphine showed a strong preference for the morphine-paired chamber. In self-administration studies, rats were trained to respond for the high efficacy mu opioid receptor agonist fentanyl on an FR5 schedule of reinforcement. Following complete dose-response determinations for fentanyl, a range of doses of MMP-2200 as well as morphine were tested. Relative to the mu agonist morphine, MMP-2200 maintained a significantly lower number of drug infusions. To begin investigating potential molecular mechanisms for the reduced side effect profile of MMP-2200, we also examined βarrestin2 (βarr2) recruitment and chronic MMP-2200 induced cAMP tolerance and super-activation at the human delta and mu receptors in vitro. MMP-2200 efficaciously recruited βarr2 to both receptors, and induced cAMP tolerance and super-activation equivalent to or greater than morphine at both receptors. The in vivo findings suggest that MMP-2200 may be less reinforcing than morphine but may have some abuse potential. The reduced side effect profile cannot be explained by reduced βarr2 recruitment or reduced cAMP tolerance and superactivation at the monomeric receptors in vitro.
To maximize fitness, breeding adults may respond to environmental processes by adjusting their progeny's sex ratios. R. A. Fisher in 1930 hypothesized that frequency-dependent selection would result in equal investment in sons and daughters over the long term, yielding a balanced sex ratio if the costs of raising a son and daughter are equal. Diverse hypotheses have tried to explain population and brood-by-brood deviations from this mean as well as annual variation by focusing on adult sex ratios, resources, abiotic conditions, and female and male quality. We collected data in 2002-2010 to explore population-level variation in nestling sex ratios in 2 migratory grassland songbird species: the Bobolink (Dolichonyx oryzivorus) and Savannah Sparrow (Passerculus sandwichensis). These species differ in migratory strategy (long-distance vs. short-distance), and morphological dimorphism. Fisher's hypothesis was rejected for Savannah Sparrows (n ¼ 684 nestlings; 39% male) but not rejected for Bobolinks (n ¼ 390 nestlings; 53.8% male). No relationship was found between nestling and adult sex ratios measured in the same year. In descriptive analyses at the brood level, male and female body size and age, and ecological conditions (temperature and precipitation) failed to predict nestling sex ratios. Although male nestlings were heavier than female nestlings and resource availability changed through the season, these factors did not influence sex ratios relative to female body size or seasonality. For Savannah Sparrows, larger broods tended to be male-biased. While we were otherwise not able to explain deviation in offspring sex ratio for Savannah Sparrows, our results suggest that the ecological and evolutionary pressures that affect sex ratios may be both species-and population-specific.
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