Functionally selective cannabinoid receptor signalling: Therapeutic implications and opportunities

Bosier, Barbara; Muccioli, Giulio G.; Hermans, Emmanuel; Lambert, Didier M.

doi:10.1016/j.bcp.2010.02.013

Cited by 166 publications

(141 citation statements)

References 95 publications

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“…Here we found that the induction of MEK 1/2 and ROCK activity is likely to be a part of the signaling mechanism accounting for the priming effect of JWH‐133. Our observations are in line with previous findings indicating the involvement of MEK1/2‐ERK activation in IL‐5 and GM‐CSF induced priming of human eosinophils 53. Moreover, MEK1/2‐ERK and ROCK signaling regulates a variety of proinflammatory cellular processes such as eosinophil migration, degranulation, and respiratory burst 38, 55 which afford the progression of eosinophilic inflammation.…”

Section: Discussionsupporting

confidence: 92%

“…Accordingly, we found that 2‐AG induced a much stronger Ca 2+ response compared to JWH‐133 52. CB 2 receptors have previously been shown to induce a G βγ ‐dependent MAPK/ERK signaling cascade 53. Here we found that the induction of MEK 1/2 and ROCK activity is likely to be a part of the signaling mechanism accounting for the priming effect of JWH‐133.…”

Section: Discussionsupporting

confidence: 50%

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Cannabinoid receptor 2 augments eosinophil responsiveness and aggravates allergen‐induced pulmonary inflammation in mice

Frei

Luschnig

Parzmair

et al. 2016

Allergy

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BackgroundAccumulation of activated eosinophils in tissue is a hallmark of allergic inflammation. The endocannabinoid 2‐arachidonoylglycerol (2‐AG) has been proposed to elicit eosinophil migration in a CB 2 receptor/Gi/o‐dependent manner. However, it has been claimed recently that this process may also involve other mechanisms such as cytokine priming and the metabolism of 2‐AG into eicosanoids. Here, we explored the direct contribution of specific CB 2 receptor activation to human and mouse eosinophil effector function in vitro and in vivo.Methods In vitro studies including CB 2 expression, adhesion and migratory responsiveness, respiratory burst, degranulation, and calcium mobilization were conducted in human peripheral blood eosinophils and mouse bone marrow‐derived eosinophils. Allergic airway inflammation was assessed in mouse models of acute OVA‐induced asthma and directed eosinophil migration.Results CB 2 expression was significantly higher in eosinophils from symptomatic allergic donors. The selective CB 2 receptor agonist JWH‐133 induced a moderate migratory response in eosinophils. However, short‐term exposure to JWH‐133 potently enhanced chemoattractant‐induced eosinophil shape change, chemotaxis, CD11b surface expression, and adhesion as well as production of reactive oxygen species. Receptor specificity of the observed effects was confirmed in eosinophils from CB 2 knockout mice and by using the selective CB 2 antagonist SR144528. Of note, systemic application of JWH‐133 clearly primed eosinophil‐directed migration in vivo and aggravated both AHR and eosinophil influx into the airways in a CB 2‐specific manner. This effect was completely absent in eosinophil‐deficient ∆dblGATA mice.ConclusionOur data indicate that CB 2 may directly contribute to the pathogenesis of eosinophil‐driven diseases. Moreover, we provide new insights into the molecular mechanisms underlying the CB 2‐mediated priming of eosinophils. Hence, antagonism of CB 2 receptors may represent a novel pharmacological approach for the treatment of allergic inflammation and other eosinophilic disorders.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 50%

Cannabinoid receptor 2 augments eosinophil responsiveness and aggravates allergen‐induced pulmonary inflammation in mice

Frei

Luschnig

Parzmair

et al. 2016

Allergy

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“…To date, the relative contribution of these two endocannabinoids and their pathways in the modulation of anxiety remains unclear. Furthermore, recent evidence suggests that CB 1 receptor signaling varies across brain regions (Bosier et al, 2010), and that diverse effects of anandamide-CB 1 receptor signaling mechanisms are evident even within the extended amygdala (Puente et al, 2011). Finally, the actions of anandamide are not restricted to CB 1 receptors, as endocannabinoids also act on CB 2 receptors (Mechoulam et al, 1995), GPR55 (Ryberg et al, 2007), transient receptor potential vanilloid type 1 channels (Melck et al, 1999;Smart et al, 2000;Zygmunt et al, 1999), and other G-protein subtypes (Glass and Felder, 1997b;Howlett, 2004).…”

Section: Discussionmentioning

confidence: 99%

RETRACTED ARTICLE: Cannabinoid Type 1 Receptor Availability in the Amygdala Mediates Threat Processing in Trauma Survivors

Pietrzak

Huang

Corsi-Travali

et al. 2014

Neuropsychopharmacol

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Attentional bias to threat is a key endophenotype that contributes to the chronicity of trauma-related psychopathology. However, little is known about the neurobiology of this endophenotype and no known in vivo molecular imaging study has been conducted to evaluate candidate receptor systems that may be implicated in this endophenotype or the phenotypic expression of trauma-related psychopathology that comprises threat (ie, re-experiencing, avoidance, and hyperarousal) and loss (ie, emotional numbing, depression/ dysphoria, generalized anxiety) symptomatology. Using the radioligand [ 11 C]OMAR and positron emission tomography (PET), we evaluated the relationship between in vivo cannabinoid receptor type 1 (CB 1 ) receptor availability in the amygdala, and performance on a dot-probe measure of attentional bias to threat, and clinician interview-based measures of trauma-related psychopathology. The sample comprised adults presenting with a broad spectrum of trauma-related psychopathology, ranging from nontrauma-exposed, psychiatrically healthy adults to trauma-exposed adults with severe trauma-related psychopathology. Results revealed that increased CB 1 receptor availability in the amygdala was associated with increased attentional bias to threat, as well as increased severity of threat, but not loss, symptomatology; greater peripheral anandamide levels were associated with decreased attentional bias to threat. A mediation analysis further suggested that attentional bias to threat mediated the relationship between CB 1 receptor availability in the amygdala and severity of threat symptomatology. These data substantiate a key role for compromised endocannabinoid function in mediating both the endophenotypic and phenotypic expression of threat symptomatology in humans. They further suggest that novel pharmacotherapies that target the CB 1 system may provide a more focused, mechanism-based approach to mitigating this core aspect of trauma-related psychopathology.

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“…The ubiquitous presence of the ECS correlates with its role as a modulator of multiple physiological processes, being a homeostatic mechanism that guarantees a fine adjustment of information processed in the brain and multiple peripheral tissues, and providing counter-regulatory mechanisms aimed at preserving the structure and function of organs [13,14].…”

Section: The Endocannabinoid Systemmentioning

confidence: 99%

Cellular and intracellular mechanisms involved in the cognitive impairment of cannabinoids

Puighermanal

Busquets-García

Maldonado

et al. 2012

Phil. Trans. R. Soc. B

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Exogenous cannabinoids, such as delta9-tetrahydrocannabinol (THC), as well as the modulation of endogenous cannabinoids, affect cognitive function through the activation of cannabinoid receptors. Indeed, these compounds modulate a number of signalling pathways critically implicated in the deleterious effect of cannabinoids on learning and memory. Thus, the involvement of the mammalian target of rapamycin pathway and extracellular signal-regulated kinases, together with their consequent regulation of cellular processes such as protein translation, play a critical role in the amnesic-like effects of cannabinoids. In this study, we summarize the cellular and molecular mechanisms reported in the modulation of cognitive function by the endocannabinoid system.

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Functionally selective cannabinoid receptor signalling: Therapeutic implications and opportunities

Cited by 166 publications

References 95 publications

Cannabinoid receptor 2 augments eosinophil responsiveness and aggravates allergen‐induced pulmonary inflammation in mice

Cannabinoid receptor 2 augments eosinophil responsiveness and aggravates allergen‐induced pulmonary inflammation in mice

RETRACTED ARTICLE: Cannabinoid Type 1 Receptor Availability in the Amygdala Mediates Threat Processing in Trauma Survivors

Cellular and intracellular mechanisms involved in the cognitive impairment of cannabinoids

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