The antinociceptive effect of acetylsalicylic acid is differently affected by a CB1 agonist or antagonist and involves the serotonergic system in rats.

AIMS: Combinations of non-steroidal anti-inflammatory drugs (NSAIDs) and cannabinoids are promising because of their potential synergistic effects in analgesia, resulting in a reduction in dosage and minimizing adverse reactions. The analgesic effect of acetylsalicylic acid (ASA), probably due to a central mechanism, also implicates changes in the central monoaminergic system. Therefore, we decided to evaluate the antinociceptive interaction between the CB(1) receptor agonist, HU210, and ASA in tests involving central pain in rats as well as the implication of the central serotonergic system thereon. MAIN METHODS: The selective CB(1) antagonist SR141716A and the potent cannabinoid agonist HU210 were evaluated alone and in combination with ASA in both algesimetric tests (hot-plate and formalin tests) and for 5-HT activity and 5-HT(2) receptor density and affinity. KEY FINDINGS: ASA or HU210 alone showed a dose-dependent effect in both tests. HU210, at an inactive dose, significantly increased the antinociceptive effect of the sub-active dose of ASA. SR141716A (1.5mg/kgi.p.) was ineffective per se and failed to modify antinociception induced by the HU210 plus ASA combination in either test. HU210 plus ASA significantly decreased the 5-HIAA/5-HT ratio and the 5-HT(2) receptor density in the frontal cortex, changes not antagonized by SR141716A. SIGNIFICANCE: The present study provides evidence that mutual potentiation of the antinociceptive effects of HU210 and ASA may, at least partly, depend on serotonergic mechanisms, with an indirect participation of cannabinodiergic mechanism. In conclusion, combinations of low doses of cannabinoids and NSAIDs may be of interest from the therapeutic point of view.

Chronic treatment with the selective NOP receptor antagonist [Nphe 1, Arg 14, Lys 15]N/OFQ-NH 2 (UFP-101) reverses the behavioural and biochemical effects of unpredictable chronic mild stress in rats.

INTRODUCTION: The present study was designed to assess the antidepressant effects of UFP-101, a selective nociceptin/orphanin FQ peptide (NOP) receptor antagonist, in a validated animal model of depression: the chronic mild stress (CMS). MATERIALS AND METHODS AND RESULTS: UFP-101 (5, 10 and 20 nmol/rat; i.c.v., once a day for 21 days) dose- and time-dependently reinstated sucrose consumption in stressed animals without affecting the same parameter in non-stressed ones. In the forced swimming test, UFP-101 reduced immobility of stressed rats from day 8 of treatment. After a 3-week treatment, rats were killed for biochemical evaluations. UFP-101 abolished increase in serum corticosterone induced by CMS and reverted changes in central 5-HT/5-HIAA ratio. The behavioural and biochemical effects of UFP-101 mimicked those of imipramine, the reference antidepressant drug, administered at the dose of 15 mg/kg (i.p.). Co-administration of nociceptin/orphanin FQ (5 nmol/rat, from day 12 to 21) prevented the effects of UFP-101. Brain-derived neurotrophic factor mRNA and protein in hippocampus were not reduced by CMS nor did UFP-101 modify these parameters. DISCUSSION AND CONCLUSION: This study demonstrated that chronic treatment with UFP-101 produces antidepressant-like effects in rats subjected to CMS supporting the proposal that NOP receptors represent a candidate target for the development of innovative antidepressant drugs.

Anxiolytic-like effect of neuropeptide S in the rat defensive burying.

Neuropeptide S (NPS) has been recently identified as the endogenous ligand of a previously orphan G-protein-coupled receptor now named NPSR. Both NPS and its receptor are expressed in the brain, where they modulate different functions. In particular, it has been demonstrated that intracerebroventricular (i.c.v.) injection of NPS in rodents increases wakefulness and promotes anxiolytic-like effects. In the present study we used the defensive burying (DB) test in rats to further investigate the action of human NPS (0.1-10 nmol, i.c.v.) on anxiety-related behaviors. Diazepam (1.5mg/kg, i.p.) and caffeine (20mg/kg, i.p.) were used in parallel experiments as standard anxiolytic and anxiogenic drugs, respectively. None of the tested drugs produced statistical differences in the latency to contact the probe, burying behavior latency, number of shocks received or immobility/freezing duration. Caffeine increased cumulative burying behavior and the buried bedding height in a statistically significant manner thus promoting anxiogenic like effects. Opposite results were obtained with diazepam that significantly reduced these behavioral parameters. The anxiolytic-like action of diazepam was mimicked by NPS that reduced cumulative burying behavior in a dose dependent manner. Collectively, robust anxiolytic-like effects were recorded in response to NPS in the DB test. These results are of particular interest since the outcome of this assay is marginally influenced by drug effects on locomotor activity. In conclusion, we provide further evidence that NPS evokes genuine anxiolytic-like effects in the rat; therefore NPSR selective agonists are worthy of development as innovative drugs for the treatment of anxiety disorders.

Influence of mirtazapine on the sexual behavior of male rats.

RATIONALE: Impairment of sexual activity is one of the most frequent side effects of antidepressant drugs. The increase in the synaptic concentrations of serotonin seems to be mainly responsible. Mirtazapine is a novel antidepressant that increases the synaptic concentrations of both noradrenaline and serotonin; moreover, it is an antagonist at 5-HT(2C) receptors, whose activation is considered to be responsible for some typical effects of serotonin on the ejaculation process (retardation of ejaculation, anorgasmia). OBJECTIVES: To study the influence of mirtazapine on copulatory performance and sexual motivation in male rats, in comparison-or in combination-with fluoxetine. METHODS: Copulatory performance was studied either in sexually experienced or in sexually naive rats; sexual motivation was studied in sexually experienced rats. Mirtazapine (1, 5 or 10 mg/kg), fluoxetine (10 mg/kg), and the combination of mirtazapine + fluoxetine (10+10 mg/kg) were subcutaneously (s.c.) administered either acutely or daily for 13 days. RESULTS: After acute administration, mirtazapine decreased mount latency (ML) and intromission latency (IL), and increased mount frequency (MF) and ejaculation latency (EL). Fluoxetine had no significant effect on any of the sexual behavior parameters. After a 13-day treatment, mirtazapine increased ML, IL and MF; fluoxetine increased ML, IL and the intercopulatory interval (ICI); the addition of mirtazapine to fluoxetine produced a reduction of ICI and an increase of MF. Moreover, mirtazapine significantly improved the performance of rats in the sexual motivation test. CONCLUSIONS: The present results show that, on the whole, the acute administration of mirtazapine improves several parameters of the copulatory performance of male rats and strongly stimulates sexual motivation, while the repeated administration produces minor, conflicting effects. This effect of mirtazapine on male rat sexual behavior is to be ascribed to the antagonism at brain alpha(2) adrenergic auto- and hetero-receptors, with consequent increased release of noradrenaline and serotonin, and antagonism at 5-HT(2C) receptors, which are involved in the negative influence of serotonin on male sexual behavior.