A role for cannabinoid receptors, but not endogenous opioids, in the antinociceptive activity of the CB2-selective agonist, GW405833

Whiteside, Garth T.; Gottshall, Susan L.; Boulet, Jamie; Chaffer, Suzanne M.; Harrison, James; Pearson, Michelle; Turchin, Paul I.; Mark, Lilly; Garrison, Augusta E.; Valenzano, Kenneth J.

doi:10.1016/j.ejphar.2005.10.043

Cited by 91 publications

(83 citation statements)

References 23 publications

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“…CB1 is found in the brain and in other tissues (Palmer et al, 2000;Kozak and Marnett, 2002;Snider et al, 2009) and has been demonstrated to be involved in the cannabinoid signaling pathway that protects against stroke in mice (Parmentier- Batteur et al, 2002;Marsicano et al, 2003;Panikashvili et al, 2005). The second receptor, CB2, is involved in inflammation, and agonists targeting CB2 are currently being developed as therapies to reduce inflammation and pain (Whiteside et al, 2005). It has recently been shown that the metabolism of AEA by CYP3A4 can form at least one product, 5,6-EET-EA, which has a significantly increased binding affinity for CB2.…”

Section: Discussionmentioning

confidence: 99%

Effects of a Commonly Occurring Genetic Polymorphism of Human CYP3A4 (I118V) on the Metabolism of Anandamide

Pratt-Hyatt¹,

Zhang²,

Snider³

et al. 2010

Drug Metab Dispos

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ABSTRACT:The endocannabinoid system plays an important role in numerous physiological processes including mood, appetite, and pain sensation. A critical compound in maintaining cannabinoid tone is the endocannabinoid anandamide (AEA). We have recently shown that AEA is metabolized by several different human cytochromes P450 (P450) to form a number of metabolites, one of which exhibits increased biological activity. CYP3A4, one of the major P450s involved in the metabolism of AEA, produces four major metabolites. One of these metabolites, 5,6-epoxyeicosatrienoic acid ethanolamide (5,6-EET-EA), exhibits a much higher affinity than AEA for the cannabinoid 2 receptor (CB-2), which leads to a marked decrease in intracellular cAMP levels in cells expressing CB-2. There are multiple human alleles of CYP3A4, and the CYP3A4.4 allele has been shown to exhibit a significant decrease in activity.Recombinant CYP3A4*4 was expressed in Escherichia coli and was demonstrated to produce 60% less 6-hydroxytestosterone than the wild-type (WT) 3A4 in a reconstituted system. The metabolism of AEA by the WT and the CYP3A4.4 variant was investigated. The mutant produced 60% less of the four EET-EA metabolites than the WT. The mutant also produced a new peak on liquid chromatography-mass spectrometry not seen with the WT, which corresponded to 19-hydroxyeicosatetraenoic acid-ethanolamide. In addition, the mutant produces four novel peaks at m/z 380, which correspond to the addition of two oxygen atoms, possibly to form a peroxide bond. These data indicate that individuals expressing the CYP3A4.4 allele may exhibit significant variations in the metabolism of AEA as well as any other compounds resembling AEA.

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Section: Discussionmentioning

confidence: 99%

Effects of a Commonly Occurring Genetic Polymorphism of Human CYP3A4 (I118V) on the Metabolism of Anandamide

Pratt-Hyatt¹,

Zhang²,

Snider³

et al. 2010

Drug Metab Dispos

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“…Complicating the issue further, Whiteside et al suggested that the anti-nociceptive effects of EDN might not be dependent on endogenous opioids [180]. Interestingly, blocking both peripheral and central opioid receptors with naltrexone in an animal model did not prevent the anti-nociceptive effect of the CB2 agonist GW405833.…”

Section: The Role Of the Endocannabinoid System In Dry Needling-mediamentioning

confidence: 99%

“…Interestingly, blocking both peripheral and central opioid receptors with naltrexone in an animal model did not prevent the anti-nociceptive effect of the CB2 agonist GW405833. Instead of stimulating the release of opioids, some authors suggest that the activation of CB2 receptors by endogenous anandmide results in anti-nociception and anti-inflammation by blocking the production and release of inflammatory cytokines such as TNF-α, IL factor and NGF [180]. Cannabinoids have been shown to inhibit the release of pro-inflammatory cytokines such as TNF-α, IL-4, IL-6, IL-8, and IL-10 from immune cells [146,181].…”

Section: The Role Of the Endocannabinoid System In Dry Needling-mediamentioning

confidence: 99%

Peripheral and Spinal Mechanisms of Pain and Dry Needling Mediated Analgesia: A Clinical Resource Guide for Health Care Professionals

Butts¹,

Dunning²

2016

Int J Phys Med Rehabil

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There are a number of biochemical, biomechanical, endocrinological and neurovascular mechanisms underpinning the anti-nociceptive and anti-inflammatory effects of dry needling (DN). While myofascial trigger points likely play a role in peripheral pain, a diagnostic tool for localizing them has not been validated, and DN studies that have targeted trigger points to elicit localized twitch responses have reported mixed results. Therefore, the mechanism responsible for DN-mediated analgesia may be more complicated. DN activates opioid-based pain reduction, mediated by endogenous cannabinoids and the sympathetic nervous system, and non-opioid pain relief via serotonin and norepinephrine from the brain stem. DN also triggers the hypothalamic-pituitary-adrenal axis centrally and the corticotropin releasing hormone-proopiomelanocortin-corticosteroid axis locally to inhibit cox-2, reducing inflammatory cytokines. Recent studies demonstrate that DN combined with mechanical and/or electrical stimulation may reverse PKC-mediated peripheral hyperalgesic priming by normalizing nociceptive channels, to include TRPV, ASIC, TTX and P2X/Y. Electrical DN (EDN) stimulates immune cells, fibroblasts and keratinocytes to release CGRP and substance-P, altering the stimulation of TTX receptors to reverse hyperalgesia. It also encourages the supraoptic nucleus to release oxytocin to quiet ASIC receptors peripherally and stimulate opioid interneurons spinally. Moreover, EDN inhibits ERK1/2 kinase pathways of inflammation in the spinal cord and stimulates Aδ fibers and N/OFQ to reverse C-fiber mediated central changes. Mechanotransduction of fibroblasts and peripheral nerves via TRPV1 and P2X/Y-mediated intracellular Ca 2+ wave propagation and subsequent activation of the nucleus accumbens inhibits spinal pain transmission via glycinergic and opioidergic interneurons. The increased ATP is metabolized to adenosine, which activates P1 purinergic receptors, events considered key to DN analgesia and rho kinase-based tissue remodeling. Mechanotransduction-mediated release of histamine further explains analgesia secondary to needling points distal to pain. DN-mediated analgesia is dependent on a number of synergistic physiologic events involving biochemical and mechanical processes in neural, connective and muscle tissue.

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“…The amount of time spent on Rotarod was recorded, and data were presented as percentage of baseline latency. Thermal (hot plate) and mechanical (von Frey) hypersensitivity assessments in inflammatory [complete Freund's adjuvant (CFA)] and neuropathic [spinal nerve ligation (SNL)] pain models (n ϭ 8-10/group) were conducted as described previously (Whiteside et al, 2005). Statistical significance was determined using a one-way ANOVA followed by least squared differences post hoc analysis (SAS Institute, Cary, NC).…”

Section: Methodsmentioning

confidence: 99%

Monoacylglycerol Lipase Activity Is a Critical Modulator of the Tone and Integrity of the Endocannabinoid System

Chanda

Gao²,

Mark³

et al. 2010

Mol Pharmacol

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210

204

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Endocannabinoids are lipid molecules that serve as natural ligands for the cannabinoid receptors CB1 and CB2. They modulate a diverse set of physiological processes such as pain, cognition, appetite, and emotional states, and their levels and functions are tightly regulated by enzymatic biosynthesis and degradation. 2-Arachidonoylglycerol (2-AG) is the most abundant endocannabinoid in the brain and is believed to be hydrolyzed primarily by the serine hydrolase monoacylglycerol lipase (MAGL). Although 2-AG binds and activates cannabinoid receptors in vitro, when administered in vivo, it induces only transient cannabimimetic effects as a result of its rapid catabolism. Here we show using a mouse model with a targeted disruption of the MAGL gene that MAGL is the major modulator of 2-AG hydrolysis in vivo. Mice lacking MAGL exhibit dramatically reduced 2-AG hydrolase activity and highly elevated 2-AG levels in the nervous system. A lack of MAGL activity and subsequent long-term elevation of 2-AG levels lead to desensitization of brain CB1 receptors with a significant reduction of cannabimimetic effects of CB1 agonists. Also consistent with CB1 desensitization, MAGL-deficient mice do not show alterations in neuropathic and inflammatory pain sensitivity. These findings provide the first genetic in vivo evidence that MAGL is the major regulator of 2-AG levels and signaling and reveal a pivotal role for 2-AG in modulating CB1 receptor sensitization and endocannabinoid tone.

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A role for cannabinoid receptors, but not endogenous opioids, in the antinociceptive activity of the CB2-selective agonist, GW405833

Cited by 91 publications

References 23 publications

Effects of a Commonly Occurring Genetic Polymorphism of Human CYP3A4 (I118V) on the Metabolism of Anandamide

Effects of a Commonly Occurring Genetic Polymorphism of Human CYP3A4 (I118V) on the Metabolism of Anandamide

Peripheral and Spinal Mechanisms of Pain and Dry Needling Mediated Analgesia: A Clinical Resource Guide for Health Care Professionals

Monoacylglycerol Lipase Activity Is a Critical Modulator of the Tone and Integrity of the Endocannabinoid System

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