This week we have a number of interesting papers. A publication looking at CB2-dependent suppression of chemotherapy-induced peripheral neuropathy; a paper on the role of CB2 in lympoid cell expansion; a review on synaptic changes in the context of cannabis use disorder; and a paper on 2-AG suppression of gastric emptying. Who doesn’t like a good paper dealing with the munchies ?
Also, in case you haven’t seen it. There was a landmark cannabis paper in CELL last week. Be sure to check it out.
Note: This is a post for cannabis scientists. A weekly curation of fresh papers that help advance our understanding of cannabis and the endocannabinoid system.
A peripheral CB2 cannabinoid receptor mechanism suppresses chemotherapy-induced peripheral neuropathy: evidence from a CB2 reporter mouse.
Lin X, Xu Z, Carey L, Romero J, Makriyannis A, Hillard CJ, Ruggiero E, Dockum M, Houk G, Mackie K, Albrecht PJ, Rice FL, Hohmann AG.
Pain. 2022 May 1;163(5):834-851.
CB2 cannabinoid receptors (CB2) are a promising therapeutic target that lacks unwanted side effects of CB1 activation. However, the cell types expressing CB2 that mediate these effects remain poorly understood. We used transgenic mice with CB2 promoter-driven expression of enhanced green fluorescent protein (EGFP) to study cell types that express CB2 and suppress neuropathic nociception in a mouse model of chemotherapy-induced peripheral neuropathy. Structurally distinct CB2 agonists (AM1710 and LY2828360) suppressed paclitaxel-induced mechanical and cold allodynia in CB2EGFP reporter mice with established neuropathy. Antiallodynic effects of AM1710 were blocked by SR144528, a CB2 antagonist with limited CNS penetration. Intraplantar AM1710 administration suppressed paclitaxel-induced neuropathic nociception in CB2EGFP but not CB2 knockout mice, consistent with a local site of antiallodynic action. mRNA expression levels of the anti-inflammatory cytokine interleukin-10 were elevated in the lumbar spinal cord after intraplantar AM1710 injection along with the proinflammatory cytokine tumor necrosis factor alpha and chemokine monocyte chemoattractant protein-1. CB2EGFP, but not wildtype mice, exhibited anti-GFP immunoreactivity in the spleen. However, the anti-GFP signal was below the threshold for detection in the spinal cord and brain of either vehicle-treated or paclitaxel-treated CB2EGFP mice. EGFP fluorescence was coexpressed with CB2 immunolabeling in stratified patterns among epidermal keratinocytes. EGFP fluorescence was also expressed in dendritic cells in the dermis, Langerhans cells in the epidermis, and Merkel cells. Quantification of the EGFP signal revealed that Langerhans cells were dynamically increased in the epidermis after paclitaxel treatment. Our studies implicate CB2 expressed in previously unrecognized populations of skin cells as a potential target for suppressing chemotherapy-induced neuropathic nociception.
doi: 10.1097/j.pain.0000000000002502. PMID: 35001054; PMCID: PMC8942871. https://pubmed.ncbi.nlm.nih.gov/35001054/
Cannabinoid receptor 2 engagement promotes group 2 innate lymphoid cell expansion and enhances airway hyperreactivity.
Hurrell BP, Helou DG, Shafiei-Jahani P, Howard E, Painter JD, Quach C, Akbari O.
J Allergy Clin Immunol. 2022 May;149(5):1628-1642.e10.
Cannabinoids modulate the activation of immune cells and physiologic processes in the lungs. Group 2 innate lymphoid cells (ILC2s) are central players in type 2 asthma, but how cannabinoids modulate ILC2 activation remains to be elucidated. Our goal was to investigate the effects of cannabinoids on ILC2s and their role in asthma. A combination of cannabinoid receptor (CB)2 knockout (KO) mice, CB2 antagonist and agonist were used in the mouse models of IL-33, IL-25, and Alternaria alternata ILC2-dependent airway inflammation. RNA sequencing was performed to assess transcriptomic changes in ILC2s, and humanized mice were used to assess the role of CB2 signaling in human ILC2s. We provide evidence that CB2 signaling in ILC2s is important for the development of ILC2-driven airway inflammation in both mice and human. We showed that both naive and activated murine pulmonary ILC2s express CB2. CB2 signaling did not affect ILC2 homeostasis at steady state, but strikingly it stimulated ILC2 proliferation and function upon activation. As a result, ILC2s lacking CB2 induced lower lung inflammation, as we made similar observations using a CB2 antagonist. Conversely, CB2 agonism remarkably exacerbated ILC2-driven airway hyperreactivity and lung inflammation. Mechanistically, transcriptomic and protein analysis revealed that CB2 signaling induced cyclic adenosine monophosphate-response element binding protein (CREB) phosphorylation in ILC2s. Human ILC2s expressed CB2, as CB2 antagonism and agonism showed opposing effects on ILC2 effector function and development of airway hyperreactivity in humanized mice.
Conclusion: Collectively, our results define CB2 signaling in ILC2s as an important modulator of airway inflammation.
doi: 10.1016/j.jaci.2021.09.037. Epub 2021 Oct 18. PMID: 34673048; PMCID: PMC9013728. https://pubmed.ncbi.nlm.nih.gov/34673048/
Synaptic changes induced by cannabinoid drugs and cannabis use disorder.
Augustin SM, Lovinger DM.
Neurobiol Dis. 2022 Jun 1;167:105670.
The legalization of cannabis in many countries, as well as the decrease in perceived risks of cannabis, have contributed to the increase in cannabis use medicinally and recreationally. Like many drugs of abuse, cannabis and cannabis-derived drugs are prone to misuse, and long-term usage can lead to drug tolerance and the development of Cannabis Use Disorder (CUD). These drugs signal through cannabinoid receptors, which are expressed in brain regions involved in the neural processing of reward, habit formation, and cognition. Despite the widespread use of cannabis and cannabinoids as therapeutic agents, little is known about the neurobiological mechanisms associated with CUD and cannabinoid drug use. In this article, we discuss the advances in research spanning animal models to humans on cannabis and synthetic cannabinoid actions on synaptic transmission, highlighting the neurobiological mechanisms following acute and chronic drug exposure. This article also highlights the need for more research elucidating the neurobiological mechanisms associated with CUD and cannabinoid drug use.
doi: 10.1016/j.nbd.2022.105670. Epub 2022 Feb 24. PMID: 35219856. https://pubmed.ncbi.nlm.nih.gov/35219856/
2-Arachidonoyl glycerol suppresses gastric emptying via the cannabinoid receptor 1-cholecystokinin signaling pathway in mice.
Ochiai K, Hirooka R, Sakaino M, Takeuchi S, Hira T.
Lipids. 2022 May;57(3):173-181.
2-Monoacylglycerol (2-MAG) is one of the digestion products of dietary lipids. We recently demonstrated that a 2-MAG, 2-arachidonoyl glycerol (2-AG) potently stimulated cholecystokinin (CCK) secretion via cannabinoid receptor 1 (CB1) in a murine CCK-producing cell line, STC-1. CCK plays a crucial role in suppressing postprandial gastric emptying. To examine the effect of 2-AG on gastric emptying, we performed acetaminophen and phenol red recovery tests under oral or intraperitoneal administration of 2-AG in mice. Orally administered 2-AG (25 mg/kg) suppressed the gastric emptying rate in mice, as determined by the acetaminophen absorption test and phenol red recovery test. Intraperitoneal administration of a cholecystokinin A receptor antagonist (0.5 mg/kg) attenuated the gastric inhibitory emptying effect. In addition, both oral (10 mg/kg) and intraperitoneal (0.5 mg/kg) administration of a CB1 antagonist counteracted the 2-AG-induced gastric inhibitory effect. Furthermore, intraperitoneal 2-AG (25 mg/kg) suppressed gastric emptying. These results indicate that 2-AG exhibits an inhibitory effect on gastric emptying in mice, possibly mediated by stimulating both CCK secretion via CB1 expressed in CCK-producing cells and acting on CB1 expressed in the peripheral nerves. Our findings provide novel insights into the 2-MAG-sensing mechanism in enteroendocrine cells and the physiological role of 2-MAG.
doi: 10.1002/lipd.12341. Epub 2022 Mar 10. PMID: 35266554. https://pubmed.ncbi.nlm.nih.gov/35266554/