Morphine Exacerbates Experimental Colitis-Induced Depression of Nesting in Mice

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.

Comparison of Chemotherapy Effects on Mechanical Sensitivity and Food-Maintained Operant Responding in Male and Female Rats

ObjectiveChemotherapies of varying classes often cause neuropathy and debilitating chemotherapy-induced neuropathic pain (CINP) sufficient to limit treatment and reduce quality of life for many patients battling cancer. There are currently no effective preventative or alleviative treatments for CINP. Preclinical models have been developed to test candidate CINP treatments; however, studies using these models rarely provide direct comparisons of effects of different chemotherapies or assess the degree to which chemotherapies produce clinically relevant signs of pain-depressed behavior.MethodsMale and female Sprague-Dawley rats received four injections of vehicle, paclitaxel, oxaliplatin, vincristine, or bortezomib on alternate days. Mechanical hypersensitivity, body weight, and food-maintained operant responding were evaluated before, during, and for up to 42 days after initiation of treatment. Morphine potency and effectiveness to reverse chemotherapy-induced effects were also evaluated.ResultsAll four chemotherapies produced dose-dependent and sustained mechanical hypersensitivity in all rats. Vincristine and oxaliplatin produced transient weight loss and decreases in food-maintained operant responding in all rats, whereas paclitaxel and bortezomib produced lesser or no effect. At four weeks after treatment, operant responding was depressed only in paclitaxel-treated males. Morphine reversed mechanical hypersensitivity in all rats but failed to reverse paclitaxel-induced depression of operant responding in males.ConclusionsChemotherapy treatments sufficient to produce sustained mechanical hypersensitivity failed to produce sustained or morphine-reversible behavioral depression in rats. Insofar as pain-related behavioral depression is a cardinal sign of CINP in humans, these results challenge the presumption that these chemotherapy-dosing regimens are sufficient to model clinically relevant CINP in rats.

Piracetam potentiates neuronal and behavioral effects of ketamine

Introduction: Ketamine has a fast, but short-term antidepressant effect. To support the therapeutic effect, repeated administrations of the drug are needed, which causes cognitive disorders. The drugs with cerebroprotective action can potentially intensify the main and weaken the side effects of drugs. Materials and methods: The impact of ketamine (5 and 20 μM), piracetam (100 μM), and their combinations on the synaptic transmission was studied on hippocampal slices in the CA1 area of rat hippocampus by means of electrophysiological methods. In behavioral experiments were aimed at studying an impact of the used drugs on the predictors which mark depressant behavior of rats: the duration of immobilization in a forced swimming test and preference for the consumption of sucrose solution (comparably with water). The behavioral experiments were performed on intact rats and rats with behavioral depression induced by chronic swimming stress. Results and discussion: Ketamine (5 and 20 μM) potentiates synaptic transmission in the radial layer of the CA1 hippocampal area. At a smaller concentration, ketamine potentiates synaptic transmission only due to the postsynaptic action, and at a greater concentration – with help of post- and presynaptic action. Piracetam (100 µM), like ketamine at a concentration of 5 μM stimulated synaptic transmission, but to a lesser degree. Ketamine at a concentration 5 μM under combined effect with piracetam induced the same effect as that at a concentration of 20 μM without piracetam, only due to a postsynaptic action. Ketamine at doses of 5 and 20 mg/kg one hour after a single systemic administration resulted in the reduced immobilization duration, but not predictors of preference for consuming a sweet solution; piracetam at a dose of 100 mg/kg under these conditions had no impact on the parameters of the rats’ behavior. The studied behavior parameters in cases of behavioral depression also changed after a single administration of ketamine at the doses of 5 and 20 mg/kg. Piracetam significantly stimulated an antidepressant action of ketamine under these circumstances. Conclusion: Piracetam potentiates a ketamine-induced enhancement of the synaptic transmission at the radial layer of the CA1 hippocampal area when investigating at the brain slices. Piracetam stimulates an antidepressant action of a single dose of ketamine in cases of behavioral depression, though it has no antidepressant effect when administered at a single dose.

Studies of the effect of cerebroprotective substances on the course of stress-induced behavioral depression

Introduction. Atrophic disturbances of neurons of the limbic structures of the brain, which lead to insufficient regulation of emotions and mood, cause depression. Substances with cerebroprotective activity have the ability to inhibit further development and even reverse atrophic damage to neurons. Materials and methods. Using electrophysiological techniques, the cerebroprotective activity of piracetam, diacamf – (±)-cis-3-(2-benzimidazolyl)-1,2,2-trimethylcyclopentanone-carboxylic acid hydrochloride and the compound R-86, or 3,2’-spiro-pyrrolo-2-oxindole, was investigated in rat hippocampal slices. In behavioral experiments, there was studied the influence of the above substances, which had been administered for 20 days, on the most important manifestations of behavioral depression in rats caused by a five-day swim stress, such as the time of immobilization in the forced swim test and the indicator of preference for consuming sucrose solution. In addition, the influence of piracetam and diacamf was studied on the effects of the classic antidepressant imipramine. Results and discussion. It was found that piracetam, diacamf and the compound R-86 in in vitro studies reduced the damage to the pyramidal hippocampal neurons caused by anoxia and aglycemia, the excitotoxic activity of N-methyl-D-aspartate and oxidative stress when hydrogen peroxide was applied to the slices. Cerebroprotective activity of the test substances, when they are systemically administered for 20 days, is linked with their antidepressant-like effect, which was manifested in a decrease in the immobilization time in the swim test and an increase in the sucrose solution consumption indicator. Co-administration of piracetam in rats potentiated antidepressant activity of imipramine, and diacamf showed additive synergism with the antidepressant. Conclusion. Substances with cerebroprotective activity in their chronic administration may show an antidepressant-like effect. Those that potentiate the action of classical anidepressants can be used in conjunction with antidepressants during episodes of exacerbation of the disease. Less active cerebroprotective drugs can be recommended during remission for its prolongation.

Antidepressant-like action of diacamphe against the background stress-induced behavioral depression

Background. It was find out the cerebroprotective properties of diacamphe – (±)-cis-3-(2’-benzimidazolyl)-1,2,2-trimethylcyclopentan-carbonic acid hydrochloride in vivo experiments in the some models of brain injury. Aim. To investigate the neuroprotective and antidepressant-like activities of diacamphe. Materials and Methods. It was investigated an impact of diacamphe on inhibition of the pyramidal neurons field synaptic potentials evoked by N-methyl-D-aspartate, procedure anoxia/neuroaglicemia, and H2O2 in the electrophysiological experiments on hippocampal slices for evaluating of diacamphe neuroprotective activity. It was explored in behavioral experiments the impacts of diacamphe and antidepressant imipramine on basic manifestations of behavioral depression evoked by five-days swimming stress – helplessness and anhedonia. Results. It was ascertained in experiments on the hippocampal slices that diacamphe especially at conditions of systemic administration diminished of injury of the pyramidal neurons synapses induced by procedure anoxya/aglicemia, oxidative stress, but not N-methyl-D-aspartate action. The chronic administration of diacamphe in dose 10 mg/kg reduced the manifestations of induced by swimming stress behavioral depression, decrease duration of immobility in forced swimming test (helplessness) and increase preference of intake of sweet solution comparably with water (dilution of anhedonia). Antidepressant-like action of diacamphe differences from action of traditional antidepressant imipramine so far as diacamphe did not diminishes immobilization duration in swimming test after single administration and by more slow developing of action. Conclusions. Diacamphe possesses neuroprotective action and therefore manifests antidepressant-like action against the background behavioral depression evoked by swimming stress.

Antidepressant-like action of diacamphe against the background stress-induced behavioral depression

Background. It was find out the cerebroprotective properties of diacamphe – (±)-cis-3-(2’-benzimidazolyl)-1,2,2-trimethylcyclopentan-carbonic acid hydrochloride in vivo experiments in the some models of brain injury. Aim. To investigate the neuroprotective and antidepressant-like activities of diacamphe. Materials and Methods. It was investigated an impact of diacamphe on inhibition of the pyramidal neurons field synaptic potentials evoked by N-methyl-D-aspartate, procedure anoxia/neuroaglicemia, and H2O2 in the electrophysiological experiments on hippocampal slices for evaluating of diacamphe neuroprotective activity. It was explored in behavioral experiments the impacts of diacamphe and antidepressant imipramine on basic manifestations of behavioral depression evoked by five-days swimming stress – helplessness and anhedonia. Results. It was ascertained in experiments on the hippocampal slices that diacamphe especially at conditions of systemic administration diminished of injury of the pyramidal neurons synapses induced by procedure anoxya/aglicemia, oxidative stress, but not N-methyl-D-aspartate action. The chronic administration of diacamphe in dose 10 mg/kg reduced the manifestations of induced by swimming stress behavioral depression, decrease duration of immobility in forced swimming test (helplessness) and increase preference of intake of sweet solution comparably with water (dilution of anhedonia). Antidepressant-like action of diacamphe differences from action of traditional antidepressant imipramine so far as diacamphe did not diminishes immobilization duration in swimming test after single administration and by more slow developing of action. Conclusions. Diacamphe possesses neuroprotective action and therefore manifests antidepressant-like action against the background behavioral depression evoked by swimming stress.