Investigation of Diacylglycerol Lipase Alpha Inhibition in the Mouse Lipopolysaccharide Inflammatory Pain Model

Abstract

Diacylglycerol lipase (DAGL) and, the major biosynthetic enzymes of the endogenous cannabinoid (endocannabinoid) 2-arachidonylglycerol (2-AG), are highly expressed in the nervous system and immune system, respectively. Genetic deletion or pharmacological inhibition of DAGL- protects against lipopolysaccharide (LPS)-induced inflammatory responses in mouse peritoneal macrophages and reverses LPS-induced allodynia in mice. To gain insight into the contribution of DAGL- in LPS-induced allodynia, we tested global knockout mice as well as DO34, a dual DAGL-/ inhibitor. Intraperitoneal administration of DO34 (30 mg/kg) significantly decreased whole-brain levels of 2-AG (∼83%), anandamide (∼42%), and arachidonic acid (∼58%). DO34 dose-dependently reversed mechanical and cold allodynia, and these antinociceptive effects did not undergo tolerance after 6 days of repeated administration. In contrast, DO34 lacked acute thermal antinociceptive, motor, and hypothermal pharmacological effects in naive mice. As previously reported, DAGL- (-/-) mice displayed a protective phenotype from LPS-induced allodynia. However, DAGL- (-/-) mice showed full allodynic responses, similar to their wild-type littermates. Interestingly, DO34 (30 mg/kg) fully reversed LPS-induced allodynia in DAGL- (+/+) and (-/-) mice, but did not affect the antinociceptive phenotype of DAGL- (-/-) mice in this model, indicating a DAGL--independent site of action. These findings suggest that DAGL- and DAGL- play distinct roles in LPS-induced nociception. Whereas DAGL- appears to be dispensable for the development and expression of LPS-induced nociception, DAGL- inhibition represents a promising strategy to treat inflammatory pain.

Broad and Region-Specific Impacts of the Synthetic Cannabinoid CP 55,940 in Adolescent and Adult Female Mouse Brains

“…Indeed, there are already groups working on developing DAGL inhibitors for metabolic disorders, after it was noted that DAGL KO animals are leaner and consume less food than WT littermates ( Janssen and van der Stelt, 2016 ). DAGL inhibitors are also being investigated for inflammatory pain ( Wilkerson et al, 2017 ), which could replicate some of the analgesic effects of CP without the abuse liability.…”

Role of p120 Catenin in Epac1-Induced Chronic Postsurgical Pain in Rats

“…Inducing inflammatory response of macrophages to produce abnormal inflammatory pain [31–33] and inducing anti-inflammatory cytokines to produce analgesia [18] might be a useful target for the development of novel therapeutics [34]. In this experiment, it was found that the infiltration and distribution of macrophages in the muscle around incisions were increased (Figure 2(d)), but there was no significant change in vascular endothelial permeability (Figure 2(a)) and the expression of p120 and Epac1 (Figure 3) in the sham group.…”

Cannabidiol as an add-on therapy to overcome the slow-onset and, possibly, resistance to antidepressant treatment: involvement of NAPE-PLD in the medial prefrontal cortex

“…Therefore, we should not discard that the increase in these non-NEAs mediators could contribute to our NAPE-PLD KD mice's (specifically in the vmPFC) behavioral outcomes. Similarly, DAGLα KO's effects have been investigated and shown to induce a region-dependent reduction in 2-AG, arachidonic acid, and derivatives and, in some regions, AEA (Schuele et al, 2020;Tanimura et al, 2010;Wilkerson et al, 2017). The CRISPR-Cas9 approach used in our study has the advantage of providing high selectivity towards our target (NAPE-PLD or DAGL) in a brain specific region different from global KO strategies (which are complicated by neurodevelopment adaptations) or the conditioned KO models (with considerable time investments and costs of housing in animal facilities).…”

“…Therefore, we should not discard that the increase in these non-NEAs mediators could contribute to our NAPE-PLD KD mice's (specifically in the vmPFC) behavioral outcomes. Similarly, DAGLα KO's effects have been investigated and shown to induce a region-dependent reduction in 2-AG, arachidonic acid, and derivatives and, in some regions, AEA (Schuele et al, 2020;Tanimura et al, 2010;Wilkerson et al, 2017). The (which was not certified by peer review) is the author/funder.…”