Characterisation of the cannabinoid receptor system in synovial tissue and fluid in patients with osteoarthritis and rheumatoid arthritis

Richardson, Denise; Pearson, Roberta; Kurian, Nisha; Latif, M.L.; Garle, Michael J.; Barrett, David A.; Kendall, David A.; Scammell, Brigitte E.; Reeve, Alya; Chapman, Victoria

doi:10.1186/ar2401

Cited by 269 publications

(298 citation statements)

References 64 publications

(63 reference statements)

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“…Our current lack of knowledge about how arthritis joint pathology impacts on the expression of cannabinoid receptors, both on peripheral nerves and on local cells within the knee joint, hinders the further interpretation of these studies at this point in time. We have demonstrated the expression of cannabinoid CB1 and CB2 receptors in the synovial tissue of patients with RA and OA [77], but the extent by which peripheral cannabinoid receptors present in the synovium modulate arthritis-induced pain remains unknown.…”

Section: Cb2 Receptor Modulation Of Spinal Immune Cell Functionmentioning

confidence: 99%

Dynamic changes to the endocannabinoid system in models of chronic pain

Sagar

Burston

Woodhams

et al. 2012

Phil. Trans. R. Soc. B

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The analgesic effects of cannabinoid ligands, mediated by CB1 receptors are well established. However, the side-effect profile of CB1 receptor ligands has necessitated the search for alternative cannabinoid-based approaches to analgesia. Herein, we review the current literature describing the impact of chronic pain states on the key components of the endocannabinoid receptor system, in terms of regionally restricted changes in receptor expression and levels of key metabolic enzymes that influence the local levels of the endocannabinoids. The evidence that spinal CB2 receptors have a novel role in the modulation of nociceptive processing in models of neuropathic pain, as well as in models of cancer pain and arthritis is discussed. Recent advances in our understanding of the spinal location of the key enzymes that regulate the levels of the endocannabinoid 2-AG are discussed alongside the outcomes of recent studies of the effects of inhibiting the catabolism of 2-AG in models of pain. The complexities of the enzymes capable of metabolizing both anandamide (AEA) and 2-AG have become increasingly apparent. More recently, it has come to light that some of the metabolites of AEA and 2-AG generated by cyclooxygenase-2, lipoxygenases and cytochrome P450 are biologically active and can either exacerbate or inhibit nociceptive signalling.

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Section: Cb2 Receptor Modulation Of Spinal Immune Cell Functionmentioning

confidence: 99%

Dynamic changes to the endocannabinoid system in models of chronic pain

Sagar

Burston

Woodhams

et al. 2012

Phil. Trans. R. Soc. B

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“…Processing of NAAA renders a cysteine residue (Cys131 in mice and rats and Cys126 in humans) the N-terminal amino acid and catalytic nucleophile. 18,21,22 Pharmacological blockade of intracellular NAAA activity results in a normalization of OEA and PEA levels, which are markedly reduced in inflammatory states, 18,23,24 and exerts profound anti-inflammatory effects in animal models. 18 These findings suggest that NAAA inhibition might represent a novel mechanistic approach to control inflammation.…”

mentioning

confidence: 99%

β-Lactones Inhibit N-acylethanolamine Acid Amidase by S-Acylation of the Catalytic N-Terminal Cysteine

Armirotti

Romeo

Ponzano

et al. 2012

ACS Med. Chem. Lett.

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ABSTRACT:The cysteine amidase N-acylethanolamine acid amidase (NAAA) is a member of the N-terminal nucleophile class of enzymes and a potential target for anti-inflammatory drugs. We investigated the mechanism of inhibition of human NAAA by substituted β-lactones. We characterized pharmacologically a representative member of this class, ARN077, and showed, using high-resolution liquid chromatography−tandem mass spectrometry, that this compound forms a thioester bond with the N-terminal catalytic cysteine in human NAAA. KEYWORDS: NAAA, cysteine amidase, covalent inhibitors, high resolution mass spectrometry, proteomics T he fatty acid ethanolamides (FAEs) are a family of bioactive lipid molecules that have attracted considerable interest due to their potential role in the control of pain, inflammation, and energy metabolism. Two structurally and functionally distinct classes of FAEs have been described. Polyunsaturated FAEs, such as arachidonoylethanolamide (anandamide) and eicosapentaenoylethanolamide, are endogenous agonists of G protein-coupled cannabinoid receptors. 1,2 These compounds are thought to act as retrograde messengers at synapses of the central nervous system and as local mediators in peripheral tissues. In the brain, anandamide-mediated signaling at CB 1 type cannabinoid receptors has been implicated in the regulation of anxiety, 3 depression, 4,5 stress-induced analgesia, 6 and nausea. 7 Outside the brain, anandamide released at sites of tissue injury is thought to control the initiation of emerging pain signals, 8,9 presumably by reducing the local release of proalgesic and proinflammatory factors from nociceptive nerve terminals. 10 The biological actions of anandamide are interrupted by a two-step deactivation process consisting of carriermediated transport into cells 11,12 followed by intracellular hydrolysis, which is catalyzed by the membrane-bound serine hydrolase, fatty acid amide hydrolase (FAAH). Inhibitors of this enzyme protect anandamide from deactivation and selectively magnify its intrinsic actions, producing an array of pharmacological effects that include reduced anxiety, depression, and pain. 13 Saturated and monounsaturated FAEs, which include oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), do not productively interact with cannabinoid receptors. These compounds are, however, potent or moderately potent agonists of nuclear peroxisome proliferator-activated receptor-α (PPAR-α), which is responsible for most of their analgesic and anti-inflammatory properties. 14−16 OEA and PEA are produced in many mammalian tissues, including neurons 17 and innate immune cells, 18 where a selective phospholipase D releases them by cleaving the membrane precursor, N-acyl-phosphatidylethanolamine. 19 They are deactivated either by FAAH, which prefers anandamide and OEA over PEA, or by NAAA, which conversely prefers PEA and OEA over anandamide. 20 Despite its functional similarity with FAAH, NAAA shares no homology with this or other enzymes of the same "amidase signature" family. Rather,...

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“…Similarly, systemic administration of the CB2 agonist, JWH133, suppressed pain and corrected deviation in circulating pro-and anti-inflammatory cytokines in the rat MIA model (43). These anti-inflammatory effects are limited by the rapid cellular uptake and degradation of endocannabinoid metabolites but can be overcome through the inhibition of the catabolic enzyme FAAH allowing longer physiological effects (35). In-vivo studies by Krustev et al (64) reported that FAAH inhibition with compound URB597 can elevate tissue concentrations of AEA by inhibiting local endocannabinoid degradation and dampen inflammatory pain in rodent models of OA.…”

Section: Was Shown That Aea Can Inhibit Tnf-α-induced Nf-κβ Activatiomentioning

confidence: 99%

“…The altered neuronal activity, also known as neuronal plasticity, is collectively believed to constitute the foundation of rheumatic pain and is characterized by hyperalgesia, an elevated noxious response to painful stimuli, and allodynia, a painful response to a normally mild and harmless stimulus. The primary components of the endocannabinoid signaling system (CB1, CB2, and FAAH) are characteristically expressed in the synovium of both osteoarthritic (OA) and rheumatoid arthritic (RA) patients, with compelling evidence to demonstrate an active participation in the pathophysiology of joint pain (35). Preclinical and clinical studies support the therapeutic application of cannabinoids in the treatment of chronic pain, and to date, patients suffering from chronic arthritic and musculoskeletal pain represent the most prevalent users of medicinal cannabis (36).…”

Section: Endocannabinoids and Arthritic Painmentioning

confidence: 99%