Functional Selectivity at Cannabinoid Receptors

Priestley, Richard S.; Glass, Michelle; Kendall, David A.

doi:10.1016/bs.apha.2017.03.005

Cited by 25 publications

(20 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Quantification of islet cAMP levels indicated that neither ligand affected basal or forskolin-stimulated cAMP production in either Gpr55 +/+ or Gpr55 −/− islets, or human islets, suggesting that it was unlikely that they were having inverse agonist effects at CB 1 receptors or signaling via G s -coupled receptors such as GPR119 or GPR6. However, given that there is evidence of biased agonist activity by cannabinoids [53] and we have shown that both ligands significantly elevated IP 1 production in isolated mouse and human islets we cannot rule out SR141716A and/or AM251 signalling through a nominally G s -coupled receptor via G q -biased signalling. The elevation in IP 1 implies GPR55-independent, G q-coupled receptor signalling by SR141716A and AM251 in islets and further studies using inhibitors of G q and PLC are required to confirm this mechanism of action in islets.…”

Section: Discussionmentioning

confidence: 81%

The cannabinoid ligands SR141716A and AM251 enhance human and mouse islet function via GPR55-independent signalling

Ruz‐Maldonado

Liu

Atanes

et al. 2020

Cell. Mol. Life Sci.

View full text Add to dashboard Cite

Aims Endocannabinoids are lipid mediators involved in the regulation of glucose homeostasis. They interact with the canonical cannabinoid receptors CB 1 and CB 2 , and it is now apparent that some cannabinoid receptor ligands are also agonists at GPR55. Thus, CB 1 antagonists such as SR141716A, also known as rimonabant, and AM251 act as GPR55 agonists in some cell types. The complex pharmacological properties of cannabinoids make it difficult to fully identify the relative importance of CB 1 and GPR55 in the functional effects of SR141716A, and AM251. Here, we determine whether SR141716A and AM251 regulation of mouse and human islet function is through their action as GPR55 agonists. Methods Islets isolated from Gpr55 +/+ and Gpr55 −/− mice and human donors were incubated in the absence or presence of 10 µM SR141716A or AM251, concentrations that are known to activate GPR55. Insulin secretion, cAMP, IP 1 , apoptosis and β-cell proliferation were quantified by standard techniques. Results Our results provide the first evidence that SR141716A and AM251 are not GPR55 agonists in islets, as their effects are maintained in islets isolated from Gpr55 −/− mice. Their signalling through G q-coupled cascades to induce insulin secretion and human β-cell proliferation, and protect against apoptosis in vitro, indicate that they have direct beneficial effects on islet function. Conclusion These observations may be useful in directing development of peripherally restricted novel therapeutics that are structurally related to SR141716A and AM251, and which potentiate glucose-induced insulin secretion and stimulate β-cell proliferation.

show abstract

Section: Discussionmentioning

confidence: 81%

The cannabinoid ligands SR141716A and AM251 enhance human and mouse islet function via GPR55-independent signalling

Ruz‐Maldonado

Liu

Atanes

et al. 2020

Cell. Mol. Life Sci.

View full text Add to dashboard Cite

show abstract

“…Although much has been learned about the impact of cannabinoid agonists on oligodendrocytes in health and disease, many questions remain unexplored, such as the cannabinoid impact on OPC local migration ( Kirby et al, 2006 ; Hughes et al, 2013 ) and glutamate signaling ( Spitzer et al, 2016 ), the oligodendrocyte’s ability to produce myelin and provide metabolic support to axons ( Zecca et al, 2004 ; Saab et al, 2013 ; Simons and Nave, 2015 ). Cannabinoid agonists also comprise structurally and functional distinct ligands ( Howlett et al, 2002 ; Pertwee et al, 2010 ; Laprairie et al, 2017 ; Priestley et al, 2017 ), and as such, it is important to characterize their pharmacological profiles in cell pathologies related to oligodendrocytes and other cell types in the neuro-immune complex. Although the impact of cannabinoid extracts on MS disease progression remains inconclusive ( Pertwee, 2007 ; Pryce et al, 2015 ), the outlook is optimistic ( Arévalo-Martin et al, 2008 ; Chiurchiu et al, 2015 , 2018 ).…”

Section: Perspectivesmentioning

confidence: 99%

The Endocannabinoid System and Oligodendrocytes in Health and Disease

et al. 2018

View full text Add to dashboard Cite

Cannabinoid-based interventions are being explored for central nervous system (CNS) pathologies such as neurodegeneration, demyelination, epilepsy, stroke, and trauma. As these disease states involve dysregulation of myelin integrity and/or remyelination, it is important to consider effects of the endocannabinoid system on oligodendrocytes and their precursors. In this review, we examine research reports on the effects of the endocannabinoid system (ECS) components on oligodendrocytes and their precursors, with a focus on therapeutic implications. Cannabinoid ligands and modulators of the endocannabinoid system promote cell signaling in oligodendrocyte precursor survival, proliferation, migration and differentiation, and mature oligodendrocyte survival and myelination. Agonist stimulation of oligodendrocyte precursor cells (OPCs) at both CB1 and CB2 receptors counter apoptotic processes via Akt/PI3K, and promote proliferation via Akt/mTOR and ERK pathways. CB1 receptors in radial glia promote proliferation and conversion to progenitors fated to become oligodendroglia, whereas CB2 receptors promote OPC migration in neonatal development. OPCs produce 2-arachidonoylglycerol (2-AG), stimulating cannabinoid receptor-mediated ERK pathways responsible for differentiation to arborized, myelin basic protein (MBP)-producing oligodendrocytes. In cell culture models of excitotoxicity, increased reactive oxygen species, and depolarization-dependent calcium influx, CB1 agonists improved viability of oligodendrocytes. In transient and permanent middle cerebral artery occlusion models of anoxic stroke, WIN55212-2 increased OPC proliferation and maturation to oligodendroglia, thereby reducing cerebral tissue damage. In several models of rodent encephalomyelitis, chronic treatment with cannabinoid agonists ameliorated the damage by promoting OPC survival and oligodendrocyte function. Pharmacotherapeutic strategies based upon ECS and oligodendrocyte production and survival should be considered.

show abstract

“…This is an exciting discovery with obvious translational significance if specific pathways can indeed be activated to reduce non-analgesic opioid signaling. For MORs and other G-protein coupled receptors, such as the Cannabinoid 1 receptor, agonists biased toward arrestin-mediated signaling rather than G-protein-dependent signaling pathways seem to produce greater adverse side effects ( 155 , 156 ). This has led to an emphasis on developing compounds that do not recruit either of the non-visual arrestin isoforms very well.…”

Section: Not All Opioid Analgesics Are the Same: Exploring Novel Pharmentioning

confidence: 99%

Pain Therapy Guided by Purpose and Perspective in Light of the Opioid Epidemic

et al. 2018

View full text Add to dashboard Cite

Prescription opioid misuse is an ongoing and escalating epidemic. Although these pharmacological agents are highly effective analgesics prescribed for different types of pain, opioids also induce euphoria, leading to increasing diversion and misuse. Opioid use and related mortalities have developed in spite of initial claims that OxyContin, one of the first opioids prescribed in the USA, was not addictive in the presence of pain. These claims allayed the fears of clinicians and contributed to an increase in the number of prescriptions, quantity of drugs manufactured, and the unforeseen diversion of these drugs for non-medical uses. Understanding the history of opioid drug development, the widespread marketing campaign for opioids, the immense financial incentive behind the treatment of pain, and vulnerable socioeconomic and physical demographics for opioid misuse give perspective on the current epidemic as an American-born problem that has expanded to global significance. In light of the current worldwide opioid epidemic, it is imperative that novel opioids are developed to treat pain without inducing the euphoria that fosters physical dependence and addiction. We describe insights from preclinical findings on the properties of opioid drugs that offer insights into improving abuse-deterrent formulations. One finding is that the ability of some agonists to activate one pathway over another, or agonist bias, can predict whether several novel opioid compounds bear promise in treating pain without causing reward among other off-target effects. In addition, we outline how the pharmacokinetic profile of each opioid contributes to their potential for misuse and discuss the emergence of mixed agonists as a promising pipeline of opioid-based analgesics. These insights from preclinical findings can be used to more effectively identify opioids that treat pain without causing physical dependence and subsequent opioid abuse.

show abstract

Functional Selectivity at Cannabinoid Receptors

Cited by 25 publications

References 44 publications

The cannabinoid ligands SR141716A and AM251 enhance human and mouse islet function via GPR55-independent signalling

The cannabinoid ligands SR141716A and AM251 enhance human and mouse islet function via GPR55-independent signalling

The Endocannabinoid System and Oligodendrocytes in Health and Disease

Pain Therapy Guided by Purpose and Perspective in Light of the Opioid Epidemic

Contact Info

Product

Resources

About