Biology subjects

Leishman, E.

Publications and source records attributed to Leishman, E..

4 recordsLinked to original sources

bioRxiv2025

Acetaminophen inhibits diacylglycerol lipase synthesis of 2-arachidonoyl glycerol: implications for nociception

SUMMARYThough acetaminophen is a ubiquitous analgesic, its mechanism of action remains unknown. Thus, even though acetaminophen causes ∼500 deaths each year in the US it has not been possible to design safer alternatives. Because endocannabinoids may have a role in acetaminophen action, we examined interactions between the two. We now report that acetaminophen inhibits the activity of diacylglycerol lipase α (DAGLα), but not DAGLβ, decreasing production of the endocannabinoid 2-arachidonoyl glycerol. This gave rise to the counterintuitive hypothesis that decreasing endocannabinoid production by DAGLαinhibitionmay be antinociceptive in certain settings. Supporting this hypothesis, we find that DAGL inhibition by RHC80267 is antinociceptive in wildtype but not CB1 knockout mice in the hotplate test. We propose 1) that activation of DAGLα may exacerbate some forms of nociception and 2) a novel mechanism for the antinociceptive actions of acetaminophen whereby acetaminophen inhibits a DAGLα/CB1-based circuit that plays a permissive role in at least one form of nociception.

neuroscience↗

bioRxiv2023

NAPE-PLD in the ventral tegmental area regulates reward events, feeding and energy homeostasis

The N-acyl phosphatidylethanolamine-specific phospholipase D (NAPE-PLD) catalyzes the production of N-acylethanolamines (NAEs), a family of endogenous bioactive lipids, which are involved in various biological processes ranging from neuronal functions to energy homeostasis and feeding behaviors. Reward-dependent behaviors depend on the dopamine (DA) transmission between the ventral tegmental area (VTA) and the nucleus accumbens (NAc) which conveys reward-values and scales reinforced behaviors. However, whether and how NAPE-PLD may contribute to the regulation of feeding and reward-dependent behaviors has not been investigated yet. This biological question is of paramount importance since NAEs are altered in obesity and metabolic disorders. Here, we show that transcriptomic meta-analysis highlights a potential role for NAPE-PLD within the VTA[->]NAc circuit. Using brain-specific invalidation approaches, we report that the integrity of NAPE-PLD is required for the proper homeostasis of NAEs within the midbrain VTA and it affects food-reward behaviors. Moreover, region-specific knock-down of NAPE-PLD in the VTA resulted in enhanced food-reward seeking and reinforced behaviors which were associated with increased in vivo DA release dynamics in response to both food and non-food-related rewards together with heightened tropism towards food consumption. Furthermore, midbrain knock-down of NAPE-PLD, which led to increased energy expenditure and adapted nutrients partitioning, elicited a relative protection against high-fat diet-mediated body fat gain and obesity-associated metabolic features. In conclusion, these findings unravel a new key role of VTA NAPE-PLD in shaping DA-dependent events, feeding behaviors and energy homeostasis, thus providing new insights on the regulation of body metabolism. Highlights- NAPE-PLD and NAEs are enriched in the VTA and regulate food-reinforced behaviors and reward processes. - NAPE-PLD scales in vivo VTA[->]NAc dopamine dynamics. - NAPE-PLD in the VTA contributes to whole-body energy balance and metabolic efficiency. - Downregulation of VTA NAPE-PLD ameliorates obesity-associated metabolic features.

neuroscience↗

bioRxiv2021

Light-induction of endocannabinoids and activation of Drosophila TRPC channels

Drosophila phototransduction represents a classical model for signaling cascades that culminate with activation of TRP channels. TRP and TRPL are the canonical TRP (TRPC) channels, which are gated by light stimulation of rhodopsin and engagement of Gq and phospholipase C{beta} (PLC). Despite decades of investigation, the mechanism of TRP activation in photoreceptor cells is unresolved. Here, using a combination of genetics, lipidomics and Ca2+ imaging, we found that light increased the levels of an abundant endocannabinoid, 2-linoleoyl glycerol (2-LG) in vivo. The elevation in 2-LG strictly depended on the PLC encoded by norpA. Moreover, this endocannabinoid upregulated TRPC-dependent Ca2+ influx in a heterologous expression system and in dissociated ommatidia from compound eyes. We propose that 2-LG is a physiologically relevant endocannabinoid that activates TRPC channels in photoreceptor cells.

neuroscience↗

bioRxiv2019

Long-Term Aberrations To Cerebellar Endocannabinoids Induced By Early-Life Stress

Studies of early-life stress traditionally focus on glucocorticoid signaling as a modulator of neurodevelopmental risk, but emerging evidence points to the role of the endocannabinoid system in long-term stress-induced neural remodeling. Existing studies on stress-induced endocannabinoid dysregulation have focused on changes to cerebrum that are temporally proximal to stressors, but little is known about temporally distal effects, especially in cerebellum, which is vulnerable to early developmental stress and is dense with cannabinoid receptors. Further, sex-specific effects of stress on cerebellar endocannabinoid tone are understudied. Following a naturalistic rodent model of early-life stress, limited bedding at postnatal days 2-9, adult (postnatal day 70) cerebellar and hippocampal endocannabinoids and related lipids and mRNA were assessed, and behavioral performance was evaluated. Regional and sex-specific effects were present at baseline and following early-life stress. Limited bedding impaired peripherally-measured basal corticosterone in adult males only. In the CNS, early-life stress (1) decreased 2-arachidonoyl glycerol and arachidonic acid in the cerebellar deep nuclei in males only; (2) decreased 2-arachidonoyl glycerol in females only in cerebellar Crus I; and (3) increased dorsal hippocampus prostaglandins in males only. Transcriptomics for cerebellar interpositus nucleus revealed substantial sex effects, with minimal effects of stress. Stress did impair novel object recognition in both sexes and social preference in females. Taken together, the cerebellar endocannabinoids system exhibits robust sex-specific differences, malleable through early-life stress and perhaps also contributing to sexual differentiation of the brain. The current study may foster future research into stress as a risk factor for cerebellar-related dysfunctions.

neuroscience↗