Comparison of the reinforcing, antinociceptive, and respiratory depressant effects of prototypical and G-protein biased mu-opioid receptor agonists in male and female Sprague-Dawley rats.

Rationale: G-protein biased mu-opioid receptor (MOR) agonists have been reported to exhibit superior therapeutic windows compared to prototypical MOR agonists when relating antinociception to respiratory depression. However, there is relatively little research on the abuse potential of G-protein biased MOR agonists in relation to other behavioral endpoints.

Objectives: The aim of the present study was to quantitatively compare the reinforcing, antinociceptive, and respiratory-depressant effects of the prototypical MOR agonists, fentanyl and oxycodone, to the G-protein biased MOR agonists, SR14968 and SR17018, in male and female rats.

Anxiolytic-like effects of an mGluR 5 antagonist and a mGluR 2/3 agonist, and antidepressant-like effects of an mGluR 7 agonist in the chick social separation stress test, a dual-drug screening model of treatment-resistant depression.

Modulation of glutamate receptors has demonstrated anxiolytic and/or antidepressant effects in rodent stress models. The chick social-separation stress paradigm exposes socially raised aves to an isolation stressor which elicits distress vocalizations (DVocs) in an attempt to re-establish contact. The model presents a state of panic during the first 5 min followed by a state of behavioral despair during the last 60 to 90 min.

Differential Effects of Cannabidiol and a Novel Cannabidiol Analog on Oxycodone Place Preference and Analgesia in Mice: an Opioid Abuse Deterrent with Analgesic Properties.

This study sought to determine whether cannabidiol (CBD) or a CBD derivative, CBD monovalinate monohemisuccinate (CBD-val-HS), could attenuate the development of oxycodone reward while retaining its analgesic effects. To determine the effect on oxycodone reward, animals were enrolled in the conditioned place preference paradigm and received either saline or oxycodone (3.0 mg/kg) in combination with either CBD or CBD-val-HS utilizing three sets of drug-/no drug-conditioning trials.

The kappa-opioid receptor agonist, triazole 1.1, reduces oxycodone self-administration and enhances oxycodone-induced thermal antinociception in male rats.

Rationale: Triazole 1.1 is a novel kappa-opioid receptor (KOR) agonist reported to produce antinociception without KOR-typical adverse effects. When combined with the mu-opioid receptor (MOR) agonist, oxycodone, triazole 1.

Role of Cannabinoids and Terpenes in Cannabis-Mediated Analgesia in Rats.

has been used for centuries in treating pain. However, the analgesic role of many of its constituents including terpenes is unknown. This research examined the contributions of terpenes (volatile oil) and cannabinoids in cannabis-mediated analgesia in rats.

Effects of Cannabidiol and a Novel Cannabidiol Analog against Tactile Allodynia in a Murine Model of Cisplatin-Induced Neuropathy: Enhanced Effects of Sub-Analgesic Doses of Morphine.

Objective: This research examined whether a cannabidiol (CBD)-opioid pharmacotherapy could attenuate cisplatin-induced tactile allodynia.

Methods: Mice (C57BL/6) were given 6 doses of 2.3 mg/kg cisplatin intraperitoneally (IP) on alternating days to induce tactile allodynia as quantified using an electric von Frey (eVF).

Effects of Cannabidiol on Morphine Conditioned Place Preference in Mice.

This study sought to determine whether the cannabis constituent cannabidiol attenuates the development of morphine reward in the conditioned place preference paradigm. Separate groups of mice received either saline or morphine in combination with one of four doses of cannabidiol using three sets of drug/no-drug conditioning trials. After drug-place conditioning, morphine mice displayed robust place preference that was attenuated by 10 mg/kg cannabidiol.

Effects of nalfurafine on the reinforcing, thermal antinociceptive, and respiratory-depressant effects of oxycodone: modeling an abuse-deterrent opioid analgesic in rats.

Rationale: Strategies to reduce the misuse of mu opioid agonists are critically needed. Previous work has shown that kappa opioid agonists can diminish the abuse-related effects and augment the antinociceptive effects of mu agonists. However, use of traditional kappa agonists is limited by their dysphoric side effects.

The effects of repeated nitroglycerin administrations in rats; modeling migraine-related endpoints and chronification.

Background: Rodent models typically use a single nitroglycerin injection to induce migraine, yet migraine in clinical populations presents as recurrent episodes. Further, these models quantify behavioral endpoints that do not align with the clinical features of episodic migraine or migraine chronification and therefore may limit translational relevance.

New Method: Rats received 5 nitroglycerin (10mg/kg/2ml), propylene glycol/ethanol vehicle, or saline injections every third day over 15days.

The effects of Sceletium tortuosum (L.) N.E. Br. extract fraction in the chick anxiety-depression model.

Ethnopharmacological Relevance: Sceletium tortuosum (L.) N.E.

Effects of Delta-9-Tetrahydrocannabinol and Cannabidiol on Cisplatin-Induced Neuropathy in Mice.

Sativex, a cannabinoid extract with a 1 : 1 ratio of tetrahydocannabinol and cannabidiol, has been shown to alleviate neuropathic pain associated with chemotherapy. This research examined whether tetrahydocannabinol or cannabidiol alone could attenuate or prevent cisplatin-induced tactile allodynia. In experiment 1, mice (C57BL/6) received eight administrations of 2.

Clinically relevant behavioral endpoints in a recurrent nitroglycerin migraine model in rats.

Background: This research sought to further validate the rat nitroglycerin (NTG) migraine model by comparing the effects of single versus recurrent NTG episodes on behavioral endpoints that mirror ICHD-3 diagnostic criteria for migraine, and to determine if the altered behavioral endpoints are reduced after administration of sumatriptan.

Methods: Separate cohorts of rats were administered NTG (10 mg/kg/2 ml) or saline (Experiment 1: single injection; Experiment 2: repeated injections; Experiment 3: repeated injections with sumatriptan [0.0, 0.

Comparative effects of Mitragyna speciosa extract, mitragynine, and opioid agonists on thermal nociception in rats.

This study sought to compare the effects of Mitragyna speciosa (Korth.) Havil. extract, alkaloids fraction, and mitragynine, a μ-opioid receptor agonist, to that of morphine and oxycodone in a test of thermal nociception.

Design, synthesis and biological evaluation of bivalent benzoxazolone and benzothiazolone ligands as potential anti-inflammatory/analgesic agents.

Benzoxazolone and benzothiazolone were used as template blocks to develop two series of dimers as anti-inflammatory and analgesic agents based on the concept of bivalent ligands. The first series (I) involved varying the carbon chain lengths extending from the piperazine core to the nitrogen atom of the dibenzo[d]oxazol-2(3H)-one or dibenzo[d]thiazol-2(3H)-one. The second series (II) was designed by changing the attachment point.

The conditioned place preference test for assessing welfare consequences and potential refinements in a mouse bladder cancer model.

Most pre-clinical analgesic efficacy assays still involve nociceptive testing in rodents. This is despite concerns as to the relevance of these tests for evaluating the pain-preventative properties of drugs. More appropriate methods would target pain rather than nociception, but these are currently not available, so it remains unknown whether animal pain equates to the negatively affective and subjective/emotional state it causes in humans.

Effects of Sceletium tortuosum in rats.

Ethnopharmacological Relevance: Broad historical and current uses in addition to diverse activity on CNS targets may make Sceletium tortuosum a useful therapeutic in a variety of clinical settings. This study sought to more broadly characterize activity of Sceletium tortuosum and mesembrine in a number of common, rodent-based assays that model nociception, depression, anxiety, ataxia, and abuse liability.

Materials And Methods: Male Sprague-Dawley were administered Sceletium tortuosum extract products and behavioral responses were evaluated in the conditioned place preference (CPP), hot plate, forced swim, elevated plus, and rotarod tests.

The effect of Salvia divinorum and Mitragyna speciosa extracts, fraction and major constituents on place aversion and place preference in rats.

Ethnopharmacological Relevance: Consumer use of botanicals has increased despite, in many instances, the paucity of research demonstrating efficacy or identifying liabilities. This research employed the place preference/aversion paradigm to characterize the psychoactive properties of Salvia divinorum extract (10, 30, 100mg/kg), salvinorin A (0.1, 0.

Identification of a treatment-resistant, ketamine-sensitive genetic line in the chick anxiety-depression model.

The introduction of pharmacotherapies for treatment-resistant depression is hindered by translational challenges with existing preclinical screening models that fail to adequately model the clinical features of this syndrome. This research sought to screen antidepressants in two selected genetic lines previously identified as stress-vulnerable and -resilient in the chick anxiety-depression model. Separate groups of socially-raised 5-6 day-old Black Australorps (stress-vulnerable) and Production Reds (stress-resilient) were administered imipramine (0-20 mg/kg), fluoxetine (0-10 mg/kg), maprotiline (0-10 mg/kg) or ketamine 0-15 mg/kg) IP (1 ml/kg) and placed into isolation for 90 min.

In vitro structure-activity relationships of aplysinopsin analogs and their in vivo evaluation in the chick anxiety-depression model.

Aplysinopsins are tryptophan-derived natural products that have been isolated from a variety of marine organisms and have been shown to possess a range of biological activities. In vitro receptor binding assays showed that of the 12 serotonin receptor subtypes, analogues showed a high affinity for the 5-HT2B and 5-HT2C receptor subtypes, with selectivity for 5-HT2B over 5-HT2C. While no conclusions could be drawn about the number and position of N-methylations, bromination at C-4 and C-5 of the indole ring resulted in greater binding affinities, with Ki's as low as 35 nM.

Strain vulnerability and resiliency in the chick anxiety-depression model.

Increasing research is focused on genetic contributions to variability in stress-related endophenotypes in humans and animal model simulations. The current study sought to identify strain vulnerabilities and resiliencies to an isolation-stressor in the chick anxiety-depression model. Nine different strains of socially raised chicks were tested in isolated or non-isolated conditions for 90 min in which distress vocalization (DVoc) rates were collected and then transformed to depression-like phase threshold (@ 25, 50, 75 and 95%) latencies.

Brain-derived neurotrophic factor response in vulnerable and resilient genetic lines in the chick anxiety-depression model.

Altered BDNF-mediated synaptogenesis is a major contributor to stress-vulnerability and depression. This study sought to determine patterns of hippocampal BDNF expression in stress-vulnerable and -resilient strains in the chick anxiety-depression model. Socially raised Black Australorp and Production Red strains were tested at 5-6 days post hatch under either 30, 60, 90, or 120 min of social separation stress; chicks tested with 2 social companions for 120 min served as controls.

Pharmacological reversal of cognitive bias in the chick anxiety-depression model.

Cognitive bias presents in clinical populations where anxious individuals adopt a more pessimistic interpretation of ambiguous aversive stimuli and depressed individuals adopt both a more pessimistic interpretation of ambiguous aversive stimuli and a less optimistic interpretation of ambiguous appetitive stimuli. These biases have been reversed by anxiolytics and antidepressants. In the current study, chicks exposed to an isolation stressor of 5-min to induce an anxiety-like state or 60-min to induce a depressive-like state were tested in a straight alley maze to a series of morphed ambiguous appetitive (chick silhouette) to aversive (owl silhouette) cues.

The effects of environmental enrichment in the chick anxiety-depression model.

As a validation step of an animal simulation, the effects of environmental enrichment were tested in the anxiety-depression model, in which socially raised chicks are placed in isolation for a 2h test period. Isolated chicks display an initial high rate of distress vocalizations, constituting the anxiety-like phase, followed by a marked decline and plateau in rates of vocalizations for the remainder of time in isolation, characterizing the depression-like phase. Four separate groups of domestic fowl chicks were group housed under enriched, impoverished (i.

Cognitive bias in the chick anxiety-depression model.

Cognitive bias is a phenomenon that presents in clinical populations where anxious individuals tend to adopt a more pessimistic-like interpretation of ambiguous aversive stimuli whereas depressed individuals tend to adopt a less optimistic-like interpretation of ambiguous appetitive stimuli. To further validate the chick anxiety-depression model as a neuropsychiatric simulation we sought to quantify this cognitive endophenotype. Chicks exposed to an isolation stressor of 5m to induce an anxiety-like or 60 m to induce a depressive-like state were then tested in a straight alley maze to a series of morphed ambiguous appetitive (chick silhouette) to aversive (owl silhouette) cues.