The peripheral cannabinoid receptor: adenylate cyclase inhibition and G protein coupling

Bayewitch, Michael; Avidor‐Reiss, Tomer; Levy, Rivka; Barg, Jacob; Mechoulam, Raphael; Vogel, Zvi

doi:10.1016/0014-5793(95)01207-u

Cited by 183 publications

(123 citation statements)

References 17 publications

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“…We demonstrated that anandamide has both antihyperalgesic and anti-edemic effects. Most studies have found that anandamide does not activate the CB 2 receptor (Facci et al, 1995;Bayewitch et al, 1995) except at very high concentrations (greater than 75 mM; Lee et al, 1995) supporting the hypothesis that anandamide's effects in the present study are mediated by the CB 1 receptor. Moreover, anandamideinduced antihyperalgesia was inhibited by the coadministration of the selective CB 1 receptor antagonist SR 141716A.…”

Section: Discussionsupporting

confidence: 84%

Cannabinoids reduce hyperalgesia and inflammation via interaction with peripheral CB1 receptors

Richardson¹,

Kilo²,

Hargreaves³

1998

Pain

456

299

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Central antinociceptive effects of cannabinoids have been well documented. However, relatively little is known about the peripheral effects of the cannabinoids on inflammation. In the present study, we evaluated the effects of peripherally administered cannabinoids on three indices of inflammation: carrageenan-induced thermal hyperalgesia, carrageenan-induced edema, and capsaicin-induced plasma extravasation. In addition, we determined the effect of cannabinoids on capsaicin-evoked neuropeptide release from isolated rat hindpaw skin. Our results indicate that cannabinoids produce antihyperalgesia via interaction with a peripheral CB 1 receptor. Peripheral, but not systemic, administration of 0.01 ng anandamide inhibited the induction of hyperalgesia. Peripheral administration of anandamide also attenuated hyperalgesia after its development via interaction with the CB 1 cannabinoid receptor subtype as indicated by its reversal with the CB 1 receptor antagonist SR 141716A. Additionally, peripheral, but not systemic, administration of 0.01 ng anandamide inhibited edema. Peripherally administered cannabinoids also interacted with CB 1 receptors to inhibit capsaicin-evoked plasma extravasation into the hindpaw. One potential mechanism for the anti-inflammatory actions of the cannabinoids is the inhibition of neurosecretion from the peripheral terminals of nociceptive primary afferent fibers. This hypothesis is supported by the finding that anandamide inhibited capsaicinevoked release of calcitonin gene-related peptide from isolated hindpaw skin. Collectively, these results indicate that cannabinoids reduce inflammation via interaction with a peripheral CB 1 receptor. A potential mechanism for this effect is the inhibition of neurosecretion from capsaicin-sensitive primary afferent fibers.

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Section: Discussionsupporting

confidence: 84%

Cannabinoids reduce hyperalgesia and inflammation via interaction with peripheral CB1 receptors

Richardson¹,

Kilo²,

Hargreaves³

1998

Pain

456

299

View full text Add to dashboard Cite

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“…Administration of SR144528 alone had no effect on microglial proliferation. Because the CB 2 receptor is a G-protein coupled receptor (GPCR) whose effects are known to be mediated through the G␣ i subunit (Bayewitch et al, 1995), we sought to demonstrate an inhibition of CB 2 receptor-mediated proliferation by concurrently treating cells with 100 ng/ml pertussis toxin, an irreversible G␣ i /G␣ o inhibitor. However, normal M-CSF-dependent proliferation (i.e., in the absence of cannabinoids) was inhibited by pertussis toxin (33% of untreated control, data not shown).…”

Section: Resultsmentioning

confidence: 99%

Cultured Rat Microglial Cells Synthesize the Endocannabinoid 2-Arachidonylglycerol, Which Increases Proliferation via a CB₂Receptor-Dependent Mechanism

et al. 2004

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Microglia, as phagocytes and antigen-presenting cells in the central nervous system, are activated in such disease processes as stroke and multiple sclerosis. Because peripheral macrophages are capable of producing endocannabinoids, we have examined endocannabinoid production in a macrophage-colony stimulating factor (M-CSF)-dependent rat microglial cell line (RTMGL1) using reversed phase high-pressure liquid chromatography and liquid chromatography-mass spectroscopy. We determined that cultured microglial cells produce the endocannabinoid 2-arachidonylglycerol (2-AG) as well as anandamide in smaller quantities. When 2-AG, but not anandamide, is added exogenously, RT-MGL1 microglia increase their proliferation. This increased proliferation is blocked by an antagonist of the CB 2 receptor N-[(1S)-endo-1,3,3-trimethyl bicyclo heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide (SR144528) and mimicked by the CB 2 receptor-specific agonist 1,1-dimethylbutyl-1-deoxy-⌬ 9 -tetrahydrocannabinol (JWH133). Accompanying the increase in proliferation seen with 2-AG is an increase in active ERK1 that is also blocked with SR144528. The RTMGL1 microglial cells, which exist in a primed state, express the CB 1 and CB 2 receptors as demonstrated by reverse transcription-polymerase chain reaction and immunostaining. The CB 2 receptor in untreated cells is expressed both at the cell surface and internally, and exposure of the cells to 2-AG significantly increases receptor internalization. These data suggest that 2-AG activation of CB 2 receptors may contribute to the proliferative response of microglial cells, as occurs in neurodegenerative disorders.

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“…For example, high concentrations of CB agonists inhibit inositol trisphosphate formation (Nah et al, 1993), and elicit the release of intracellular calcium (Felder et al, 1992; as well as the liberation of arachidonic acid (Howlett, 1995). One proposed explanation for these receptor-independent eects is that the cannabinoids incorporate into the membrane and directly modulate the activity of integrated membrane proteins such as Ga i (Bayewitch et al, 1995). Independently of whether or not the eects of D…”

Section: Discussionmentioning

confidence: 99%

The extracellular regulated kinases (ERK) 1/2 mediate cannabinoid‐induced inhibition of gap junctional communication in endothelial cells

Brandes

Popp

Ott

et al. 2002

British J Pharmacology

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1 Cannabinoids are potent inhibitors of endothelium-derived hyperpolarizing factor (EDHF)-mediated relaxations. We set out to study the mechanism underlying this eect and the possible role of cannabinoid-induced changes in intercellular gap junction communication. -THC prevented both the bradykinin-induced hyperpolarization and the nitric oxide and prostacyclin-independent relaxation of pre-contracted rings of porcine coronary artery. These eects were prevented by PD98059 as well as U0126. 5 In the absence of D 9 -THC, neither PD98059 nor U0126 aected the NO-mediated relaxation of coronary artery rings but both substances induced a leftward shift in the concentration ± relaxation curve to bradykinin when diclofenac and N o nitro-L-arginine were present. Moreover, PD98059 and U0126 prolonged the bradykinin-induced hyperpolarization of porcine coronary arteries, without aecting the magnitude of the response. 6 These results indicate that the cannabinoid-induced activation of ERK1/2, which leads to the phosphorylation of connexin 43 and inhibition of gap junctional communication, may partially account for the D 9-THC-induced inhibition of EDHF-mediated relaxation. Moreover, the activation of ERK1/2 by endothelial cell agonists such as bradykinin, appears to exert a negative feedback inhibition on EDHF-mediated responses.

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The peripheral cannabinoid receptor: adenylate cyclase inhibition and G protein coupling

Cited by 183 publications

References 17 publications

Cannabinoids reduce hyperalgesia and inflammation via interaction with peripheral CB1 receptors

Cannabinoids reduce hyperalgesia and inflammation via interaction with peripheral CB1 receptors

Cultured Rat Microglial Cells Synthesize the Endocannabinoid 2-Arachidonylglycerol, Which Increases Proliferation via a CB₂Receptor-Dependent Mechanism

The extracellular regulated kinases (ERK) 1/2 mediate cannabinoid‐induced inhibition of gap junctional communication in endothelial cells

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The peripheral cannabinoid receptor: adenylate cyclase inhibition and G protein coupling

Cited by 183 publications

References 17 publications

Cannabinoids reduce hyperalgesia and inflammation via interaction with peripheral CB1 receptors

Cannabinoids reduce hyperalgesia and inflammation via interaction with peripheral CB1 receptors

Cultured Rat Microglial Cells Synthesize the Endocannabinoid 2-Arachidonylglycerol, Which Increases Proliferation via a CB2Receptor-Dependent Mechanism

The extracellular regulated kinases (ERK) 1/2 mediate cannabinoid‐induced inhibition of gap junctional communication in endothelial cells

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Cultured Rat Microglial Cells Synthesize the Endocannabinoid 2-Arachidonylglycerol, Which Increases Proliferation via a CB₂Receptor-Dependent Mechanism