THC Vapor Inhalation Attenuates Hyperalgesia in Rats Using a Chronic Inflammatory Pain Model.

Humans use cannabinoid drugs to alleviate pain. As cannabis and cannabinoids are legalized in the United States for medicinal and recreational use, it has become critical to determine the potential utilities and harms of cannabinoid drugs in individuals living with chronic pain. Here, we tested the effects of repeated ∆9-tetrahydrocannabinol (THC) vapor inhalation on thermal nociception and mechanical sensitivity, in adult male and female Wistar rats using a chronic inflammatory pain model (ie, treated with complete Freund's adjuvant [CFA]). We report that repeated THC vapor inhalation rescues thermal hyperalgesia in males and females treated with CFA and also reduces mechanical hypersensitivity in CFA males but not females. Many of the antihyperalgesic effects of chronic THC vapor were still observable 24 hours after cessation of the last THC exposure. We also report plasma levels of THC and its major metabolites, some of which are cannabinoid type-1 receptor agonists, after the first and tenth days of THC vapor inhalation. Finally, we report that systemic administration of the cannabinoid type-1 receptor inverse agonist AM251 (1 mg/kg, I.P.) blocks the antihyperalgesic effects of THC vapor in males and females. These data provide a foundation for future work that will explore the cells and circuits underlying the antihyperalgesic effects of THC vapor inhalation in individuals with chronic inflammatory pain. PERSPECTIVE: Cannabinoids are thought to have potential utility in the treatment of chronic pain, but few animal studies have tested the effects of chronic THC or cannabis in animal models of chronic pain. We tested the effects of repeated THC vapor inhalation on chronic pain-related outcomes in male and female animals.

Effects of prenatal THC vapor exposure on body weight, glucose metabolism, and feeding behaviors in chow and high-fat diet fed rats.

BACKGROUND: 4-20% of people report using cannabis during pregnancy, thereby it is essential to assess the associated risks. There is some evidence that prenatal cannabis exposure (PCE) may be associated with increased risk for developing of obesity and diabetes later in life, however this has not been well explored under controlled conditions. The aim of this study was to use a translational THC vapor model in rodents to characterize the effects of PCE on adiposity, glucose metabolism, and feeding patterns in adulthood, with focus on potential sex differences. METHODS: Pregnant Sprague Dawley rats were exposed to vaporized THC (100 mg/ml) or control (polyethylene glycol vehicle) across the entire gestational period. Adult offspring from PCE (n = 24) or control (n = 24) litters were subjected to measures of adiposity, glucose metabolism and feeding behavior. Rats were then placed onto special diets (60% high-fat diet [HFD] or control 10% low fat diet [LFD]) for 4-months, then re-subjected to adiposity, glucose metabolism and feeding behavior measurements. RESULTS: PCE did not influence maternal weight or food consumption but was associated with transient decreased pup weight. PCE did not initially influence bodyweight or adiposity, but PCE did significantly reduce the rate of bodyweight gain when on HFD/LFD, regardless of which diet. Further, PCE had complex effects on glucose metabolism and feeding behavior that were both sex and diet dependent. No effects of PCE were found on plasma leptin or insulin, or white adipose tissue mass. CONCLUSIONS: PCE may not promote obesity development but may increase risk for diabetes and abnormal eating habits under certain biological and environmental conditions. Overall, this data enhances current understanding of the potential impacts of PCE.

Pharmacokinetics and central accumulation of delta-9-tetrahydrocannabinol (THC) and its bioactive metabolites are influenced by route of administration and sex in rats.

Up to a third of North Americans report using cannabis in the prior month, most commonly through inhalation. Animal models that reflect human consumption are critical to study the impact of cannabis on brain and behaviour. Most animal studies to date utilize injection of delta-9-tetrahydrocannabinol (THC; primary psychoactive component of cannabis). THC injections produce markedly different physiological and behavioural effects than inhalation, likely due to distinctive pharmacokinetics. The current study directly examined if administration route (injection versus inhalation) alters metabolism and central accumulation of THC and metabolites over time. Adult male and female Sprague-Dawley rats received either an intraperitoneal injection or a 15-min session of inhaled exposure to THC. Blood and brains were collected at 15, 30, 60, 90 and 240-min post-exposure for analysis of THC and metabolites. Despite achieving comparable peak blood THC concentrations in both groups, our results indicate higher initial brain THC concentration following inhalation, whereas injection resulted in dramatically higher 11-OH-THC concentration, a potent THC metabolite, in blood and brain that increased over time. Our results provide evidence of different pharmacokinetic profiles following inhalation versus injection. Accordingly, administration route should be considered during data interpretation, and translational animal work should strongly consider using inhalation models.

Comparison of the Time-Dependent Changes in Immediate Early Gene Labeling and Spine Density Following Abstinence From Contingent or Non-contingent Chocolate Pellet Delivery.

Rationale: Incubation of craving is a phenomenon whereby responding for cues associated with a reward increases over extended periods of abstinence. Both contingent and non-contingent behavioral designs have been used to study the incubation of craving phenomenon with differing results. The present study directly compares behavioral and neural changes following contingent or non-contingent administration of chocolate flavored pellets. Objective: The current study examined whether an incubation of craving response would be observed at the behavioral and neural levels following delays of abstinence from chocolate pellets in a contingent or non-contingent reinforcement design. Methods: Rats were trained for 10 days to bar press for chocolate pellets (contingent) or received chocolate pellets in a non-contingent design (classical conditioning). Groups were then subjected to abstinence from the reward for 24 h, 7, 14 or 28 days at which point they were tested for responding for reward associated cues. Following the test, brains from all rats were processed and assessed for c-Fos and FosB labeling as well as dendritic spine density in the nucleus accumbens (NAc). Results: Behavioral measures during the test (lever presses, food hopper entries and locomotor activity) revealed similar behavioral outcomes across all delays indicating the lack of an incubation of craving response on both the contingent and non-contingent designs. Overall, labeling of c-Fos in the NAc was lower for the non-contingent group compared to the operant-trained and food restricted control. Compared to the operant-trained and non-trained control groups, a significantly reduced FosB labeling was noted in the NAc of the classically conditioned groups across all abstinence periods. Spine density in the NAc was elevated in both the classically and operant conditioned compared to the food-restricted, non-trained controls. Conclusions: Chocolate pellet reward did not result in incubation of craving but did produce behavioral learning that was associated with increased spine density. This suggests that chocolate pellet administration results in long-term structural and functional changes that are present for at least 28 days following abstinence. Contingent and non-contingent administration resulted in differential immediate early gene labeling in the NAc, but the functional significance of this has yet to be elucidated.