Birmingham, L. | bioRxiv Science

bioRxiv2024

Elevating levels of the endocannabinoid 2-arachidonoylglycerol blunts opioid reward but not analgesia

Converging findings have established that the endocannabinoid (eCB) system serves as a possible target for the development of new treatments for pain as a complement to opioid-based treatments. Here we show in male and female mice that enhancing levels of the eCB, 2-arachidonoylglycerol (2-AG), through pharmacological inhibition of its catabolic enzyme, monoacylglycerol lipase (MAGL), either systemically or in the ventral tegmental area (VTA) with JZL184, leads to a substantial attenuation of the rewarding effects of opioids in male and female mice using conditioned place preference and self-administration paradigms, without altering their analgesic properties. These effects are driven by CB1 receptors (CB1Rs) within the VTA as VTA CB1R conditional knockout, counteracts JZL184s effects. Conversely, pharmacologically enhancing the levels of the other eCB, anandamide (AEA), by inhibition of fatty acid amide hydrolase (FAAH) has no effect on opioid reward or analgesia. Using fiber photometry with fluorescent sensors for calcium and dopamine (DA), we find that enhancing 2-AG levels diminishes opioid reward-related nucleus accumbens (NAc) activity and DA neurotransmission. Together these findings reveal that 2-AG counteracts the rewarding properties of opioids and provides a potential adjunctive therapeutic strategy for opioid-related analgesic treatments.

neuroscience↗

bioRxiv2023

Exposure to early life stress impairs weight loss maintenance success in mice.

Early life stress increases obesity risk, but its impact on weight loss maintenance is unknown. Mice underwent neonatal maternal separation (NMS) from 0-3 weeks and were weaned onto high fat sucrose diet (HFSD) from 3-20 weeks. Calorie-restricted weight loss on a low fat sucrose diet (LFSD) occurred over 2 weeks to induce a 20% loss in body weight, which was maintained for 6 weeks. After weight loss, half the mice received running wheels (EX) the other half remained sedentary (SED). Mice were then fed ad libitum on HFSD or LFSD for 10 weeks and allowed to regain body weight. NMS mice had greater weight regain, total body weight and adiposity compared to naive mice. During the first week of refeeding, NMS mice had increased food intake and were in a greater positive energy balance than naive mice, but total energy expenditure was not affected by NMS. Female mice were more susceptible to NMS-induced effects, including increases in adiposity. NMS and naive females were more susceptible to HFSD-induce weight regain. Exercise was beneficial in the first week of regain in male mice, but long-term only those on LFSD benefited from EX. As expected, HFSD led to greater weight regain than LFSD.

physiology↗