Behavioural Pharmacology最新文献

The stressful experiences, by triggering a cascade of hormonal and neural changes, can produce antinociception commonly referred to as stress-induced antinociception (SIA). Orexin neuropeptides have an essential role in stress responses and pain modulation. The dentate gyrus receives orexinergic projections and has been shown to be involved in pain processing. The current study investigated the possible role of orexin-1 and orexin-2 receptors (OX1r and OX2r, respectively) within the dentate gyrus in SIA in a rat model of formalin-induced pain behavior in one hind paw. Male Wistar rats weighing 230-250 g underwent stereotaxic surgery and a cannula was implanted in their brains, above the dentate gyrus region. Either SB334867 or TCS OX2 29 (OX1r and OX2r antagonists, respectively) was microinjected into the dentate gyrus region at a range of doses at 1, 3, 10, and 30 nmol (control group received DMSO 12% as vehicle), 5 min before the forced swim stress (FSS) exposure. The formalin test was performed to assess pain-related behaviors. The results indicated that FSS exposure relieves pain-related behavior in the early and late phases of the formalin test. Blockade of intra-dentate gyrus OX1 or OX2 receptors reduced the antinociceptive responses induced by FSS in the formalin test, with more impact during the late phase. Our findings support the potential role of intra-dentate gyrus orexin receptors as target sites of orexin neurons in painful and stressful situations. Therefore, understanding the exact mechanisms of SIA and the role of the orexinergic system in this phenomenon can lead to identifying the strategies to guide future research and offer a new approach to discovering new pain therapeutic agents.

Indole-3-acetic acid is a common naturally occurring auxin in plants. A synthesized derivative of this compound, 4-(2,4-difluorophenyl)-2-(1H-indol-3-yl)-4-oxobutanoic acid also called mitochonic acid 5 (MA-5), has shown to increase the survival ratio of fibroblasts from patients with mitochondrial disease under stress-induced conditions. Further studies verified its efficacy in pathological models, such as an ischemia-reperfusion model, possibly by increasing ATP production. However, the efficacy of MA-5 in mental disorders, such as anxiety, schizophrenia, and autism spectrum disorders (ASD), has not been investigated. Our study focused on examining the effect of MA-5 in a mouse model of ASD induced by prenatal exposure to valproic acid (VPA). VPA exposure significantly deteriorated the level of anxiety and exploratory behavior in an open field test. We fed mice an MA-5-containing diet for 5 weeks and observed an improvement in the above behavior in the MA-5-fed groups. The efficacy of MA-5 was also observed in the elevated plus maze and three-chambered tests. These findings suggest that MA-5 could potentially be used to treat ASD, especially in patients with mitochondrial dysfunction.

Nicotine use is a continuing public health concern. Smokers are more likely to make risky or maladaptive decisions compared to nonsmokers, so the relation between nicotine and risky choice warrants further investigation. Risky choice can be operationally defined as the choice for a larger, uncertain reinforcer over a smaller, certain reinforcer and can be assessed through a probability-discounting procedure. Acute nicotine administration has been shown to alter risky choice, but because the everyday smoker uses nicotine repeatedly, more research on chronic administration is needed and would allow for assessment of tolerance or sensitization of any effects. The present study examined effects of acute and repeated nicotine administration on probability discounting. Sprague-Dawley rats were used as subjects and the probability-discounting task involved discrete-trial choices between a small, certain reinforcer and a larger, uncertain reinforcer. The probability of larger-reinforcer delivery decreased across blocks within each session. Acute nicotine (0.1-1.0 mg/kg) administration dose-dependently increased risky choice, increased lose-stay ratios (a measure of response perseveration), and decreased reinforcement frequency. Tolerance to nicotine's effects on larger-reinforcer choice was observed after repeated 1.0 mg/kg nicotine administration. The results of the present study add to the existing literature that acute nicotine administration increases risky choice and demonstrates that tolerance to this effect develops after chronic exposure to the drug. Possible behavioral mechanisms behind this effect are discussed, as are suggestions for future research on nicotine and risky choice.

Berberine is an isoquinoline alkaloid naturally produced by several types of plants. Berberine has extensive pharmacological effects, such as anti-diabetic, anti-inflammatory, and antioxidant effects. In the current study, we assess the antinociceptive effects of berberine and its association with the l -arginine ( l -Arg)/NO/cGMP/K ATP channel pathway via intraplantar administration in rats. To examine the antinociceptive properties of berberine, the formalin test was conducted. The number of rat paw flinches was counted for an h. l -Arg (precursor of nitric oxide, 3-30  μ g/paw), l -NAME (NO synthase inhibitor, 10 and 100  μ g/paw), methylene blue (guanylyl cyclase inhibitor, 100 and 200  μ g/paw), and glibenclamide (ATP-sensitive potassium channel blocker, 10 and 30  μ g/paw) were locally injected, respectively, into the right hind paws of rats as a pre-treatment before berberine injection to understand how the l -Arg/NO/cGMP/K ATP pathway plays a role in the antinociceptive effect of berberine. The ipsilateral injection of berberine into the right paw (0.1-10 0   μ g/paw) showed a dose-dependent antinociceptive effect in both the first and second phases of the formalin test, almost similar to morphine (25  μ g/paw). Intraplantar injection of l -Arg (30 µg/paw) increased the antinociceptive effect of berberine in the second phase. In addition, injection of l -NAME, methylene blue, and glibenclamide caused a reduction in the antinociceptive effect of berberine throughout the second phase in a dose-dependent manner. However, the antinociceptive effects of berberine in the first phase of the rat formalin test were not affected by this pathway. As a novel local antinociceptive agent, berberine can exert a peripheral antinociceptive effect via the l -Arg/NO/cGMP/K ATP channel pathway.

Many structures of the central nervous system recruit different neurotransmitters in pain processing. This study focused on the contribution of histamine and its H 1 receptors in the ventral pallidum (VP) in mediating pain-triggered behaviors. Intra-VP microinjection of histamine and 2-pyridylethylamine (2-PEA, a histamine H 1 receptor agonist) at the same doses of 0.5 and 1 µg/200 nl reduced both the first and second phases of licking/biting duration as well as flinching number induced by intra-plantar (ipl) injection of formalin (2.5%, 50 µl). Premicroinjection of mepyramine (a histamine H 1 antagonist, 2 µg/200 nl) into the VP antagonized the suppressive effects of 1 µg/200 nl histamine and 2-PEA on licking/biting and flinching behaviors. The possible mechanisms of the above-mentioned pain-reducing effects were followed by intra-VP and intrathecal administration of naloxone (an opioid receptor antagonist). Naloxone (2 µg/200 nl) preadministration into the VP inhibited attenuating effects of histamine and 2-PEA on both the licking/biting and flinching behaviors, whereas intrathecal injection of naloxone only inhibited their suppressing effects on flinching behavior. None of the treatments used in this study altered the animal's motor activity. The obtained results may reveal the role of histamine and its activated H 1 receptor in the VP in suppressing the pain behaviors caused by formalin. Opioid receptors in the VP and spinal cord may contribute to these functions.

In 2016, the National Institutes of Health mandated the use of both male and female mice in funded research. The use of both sexes is an important variable to consider; however, it comes with negative consequences such as increased animal expenses. One way to combat these negatives is to explore the option of using a within-subjects design (repeated measures) in behavioral assays that historically use a between-subjects design. Our study aimed to determine if a within-subjects design can be utilized in the marble burying assay. The marble burying assay is used as a tool for screening putative anxiolytic compounds as the assay is thought to measure obsessive-compulsive disorder- or anxiety-like behaviors. First, we compared the effects of sex and digging medium (corn cob or Sani Chip) on the number of marbles buried using CD-1 mice. Second, we determined if mice would continue to bury marbles after repeated exposures to the test arena. Lastly, we tested three positive controls (buspirone, ketamine, and fluoxetine). We found that mice buried significantly more marbles within Sani Chip digging medium, and no sex differences were observed. Next, the number of marbles buried and locomotor activity remained consistent across four test sessions. The positive controls buspirone (3.2-10 mg/kg) ketamine (32 mg/kg), and fluoxetine (10 mg/kg) decreased the number of marbles buried using the within-subjects design. These data suggest that a within-subjects design is optimal for the marble burying assay as it will reduce the number of animals and increase statistical power.