Effects of Ketoprofen and Morphine on Pain-Related Depression of Nestlet Shredding in Male and Female Mice

Garner, Jamani; Marshall, Laura S; Boyer, Nathaniel M; Alapatt, Vinaya; Miller, Laurence L.

doi:10.3389/fpain.2021.673940

Cited by 12 publications

(9 citation statements)

References 40 publications

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“…Figures 13 , 14 show the effect of daily administration of 3.2 or 10 mg/kg ketoprofen on TNBS-induced depression of nesting. Note that effects of ketoprofen alone were not tested here because previous studies have found no effect of these ketoprofen doses on nesting in mice ( 5 – 7 ). Analysis of the time course of nesting on each day indicated that unlike morphine neither dose of ketoprofen altered TNBS-induced nesting depression on any day ( Figure 13 ).…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, nesting in mice can also be depressed by some models of experimental pain, such as intraperitoneal injection of dilute lactic acid (IP acid) as a model of acute visceral pain. IP acid-induced nesting depression is alleviated by both mu opioid receptor (MOR) agonist analgesics and non-steroidal antiinflammatory drugs (NSAIDs) (5)(6)(7).…”

Section: Introductionmentioning

confidence: 99%

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Morphine Exacerbates Experimental Colitis-Induced Depression of Nesting in Mice

et al. 2021

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Opioids and non-steroidal anti-inflammatory drugs (NSAIDs) are excellent analgesics, but recent clinical evidence suggests that these drugs might worsen disease severity in Crohn's disease patients, limiting their clinical utility for treating Inflammatory Bowel Disease (IBD). One indicator of change in well-being from conditions such as IBD is behavioral depression and disruption to activities of daily living. Preclinical measures of behavioral depression can provide an indicator of changes in quality of life and subsequent modification by candidate analgesics. In mice, nesting is an adaptive unconditioned behavior that is susceptible to disruption by noxious stimuli, and some types of pain related nesting depression are responsive to opioid and NSAID analgesics. Here we show that a 2, 4, 6-trinitrobenzene sulfonic acid (TNBS) model of experimental colitis depresses nesting behavior in mice, and we evaluated effects of morphine, an opioid, and ketoprofen, a NSAID, on TNBS-induced nesting depression. In Swiss Webster mice, TNBS significantly reduced nesting that peaked on Day 3 and recovered in a time-dependent manner with complete recovery by Day 7. In the absence of colonic inflammation, daily treatment with morphine (1–10 mg/kg) did not decrease nesting except at 10mg/kg/day. However, in TNBS-treated mice 3.2 mg/kg/day morphine significantly exacerbated TNBS-induced nesting depression and delayed recovery. While 3.2 mg/kg/day morphine alone did not alter locomotor activity and TNBS-induced depression of locomotion recovered, the combination of TNBS and 3.2 mg/kg/day morphine significantly attenuated locomotion and prevented recovery. Daily treatment with 3.2 or 10 mg/kg ketoprofen in TNBS-treated mice did not prevent depression of nesting. These data suggest that opioid analgesics but not NSAIDS worsen colonic inflammation-induced behavioral depression. Furthermore, these findings highlight the importance of evaluating analgesic effects in models of colonic inflammation induced depression of behavior.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Morphine Exacerbates Experimental Colitis-Induced Depression of Nesting in Mice

et al. 2021

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“…As a result, the development of novel, selective, low-efficacy MOR agonists may represent a promising path for analgesic drug development ( 32 – 34 ). MOR efficacy may be especially relevant for opioid effects in assays of pain-depressed behavior, where opioids can produce competing effects that include both analgesia (which alleviates pain-related behavioral depression and increases rates of the target behavior) and motor impairment (which can reduce rates of the target behavior and obscure analgesic restoration of pain-depressed behavior) ( 19 , 34 , 35 ). Accordingly, we manipulated MOR efficacy by testing both (a) a set of single-molecule opioids with decreasing MOR efficacy (fentanyl > buprenorphine > naltrexone) ( 34 , 36 , 37 ), and (b) a series of fixed-proportion fentanyl/naltrexone mixtures that vary in net MOR efficacy as described previously ( 36 , 38 – 40 ).…”

Section: Introductionmentioning

confidence: 99%

Climbing behavior by mice as an endpoint for preclinical assessment of drug effects in the absence and presence of pain

et al. 2023

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This study evaluated climbing in mice as a tool to assess the expression and treatment of pain-related behavioral depression in male and female ICR mice. Mice were videotaped during 10-min sessions in a vertical plexiglass cylinder with wire mesh walls, and “Time Climbing” was scored by observers blind to treatments. Initial validation studies demonstrated that baseline climbing was stable across repeated days of testing and depressed by intraperitoneal injection of dilute lactic acid (IP acid) as an acute pain stimulus. Additionally, IP acid-induced depression of climbing was blocked by the positive-control non-steroidal anti-inflammatory drug (NSAID) ketoprofen but not by the negative control kappa opioid receptor agonist U69593. Subsequent studies examined effects of single-molecule opioids (fentanyl, buprenorphine, naltrexone) and of fixed-proportion fentanyl/naltrexone mixtures (10:1, 3.2:1, and 1:1) that vary in their efficacy at the mu opioid receptor (MOR). Opioids administered alone produced a dose- and efficacy-dependent decrease in climbing, and fentanyl/naltrexone-mixture data indicated that climbing in mice is especially sensitive to disruption by even low-efficacy MOR activation. Opioids administered as a pretreatment to IP acid failed to block IP acid-induced depression of climbing. Taken together, these findings support the utility of climbing in mice as an endpoint to evaluate candidate-analgesic effectiveness both to (a) produce undesirable behavioral disruption when the test drug is administered alone, and (b) produce a therapeutic blockade of pain-related behavioral depression. The failure of MOR agonists to block IP acid-induced depression of climbing likely reflects the high sensitivity of climbing to disruption by MOR agonists.

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“…36,46 Furthermore, test duration and time of day are not consistent between protocols. 35 It is, therefore, possible that a different nesting protocol after SNI could reveal a phenotype as others have already shown across different pain-related models. 3,9,47,53 The same is true for our sucrose preference results (Fig.…”

Section: Discussionmentioning

confidence: 94%

Spared nerve injury decreases motivation in long-access homecage-based operant tasks in mice

Norris,

Becker,

Bilbily

et al. 2023

Pain

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Neuropathic pain causes both sensory and emotional maladaptation. Preclinical animal studies of neuropathic pain-induced negative affect could result in novel insights into the mechanisms of chronic pain. Modeling pain–induced negative affect, however, is variable across research groups and conditions. The same injury may or may not produce robust negative affective behavioral responses across different species, strains, and laboratories. Here, we sought to identify negative affective consequences of the spared nerve injury model on C57BL/6J male and female mice. We found no significant effect of spared nerve injury across a variety of approach-avoidance conflict, hedonic choice, and coping strategy assays. We hypothesized these inconsistencies may stem in part from the short test duration of these assays. To test this hypothesis, we used the homecage-based Feeding Experimentation Device version 3 to conduct 12-hour, overnight progressive ratio testing to determine whether mice with chronic spared nerve injury had decreased motivation to earn palatable food rewards. Our data demonstrate that despite equivalent task learning, spared nerve injury mice are less motivated to work for a sugar pellet than sham controls. Furthermore, when we normalized behavioral responses across all the behavioral assays we tested, we found that a combined normalized behavioral score is predictive of injury state and significantly correlates with mechanical thresholds. Together, these results suggest that homecage-based operant behaviors provide a useful platform for modeling nerve injury-induced negative affect and that valuable pain-related information can arise from agglomerative data analyses across behavioral assays—even when individual inferential statistics do not demonstrate significant mean differences.

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Effects of Ketoprofen and Morphine on Pain-Related Depression of Nestlet Shredding in Male and Female Mice

Cited by 12 publications

References 40 publications

Morphine Exacerbates Experimental Colitis-Induced Depression of Nesting in Mice

Morphine Exacerbates Experimental Colitis-Induced Depression of Nesting in Mice

Climbing behavior by mice as an endpoint for preclinical assessment of drug effects in the absence and presence of pain

Spared nerve injury decreases motivation in long-access homecage-based operant tasks in mice

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