Paradoxical effects of the cannabinoid CB2 receptor agonist GW405833 on rat osteoarthritic knee joint pain

Schuelert, Niklas; Zhang, C.; Mogg, Adrian J.; Broad, Lisa M.; Hepburn, Deena L.; Nisenbaum, Eric S.; Johnson, Michael P.; McDougall, Jason J.

doi:10.1016/j.joca.2010.09.005

Cited by 70 publications

(69 citation statements)

References 47 publications

(26 reference statements)

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“…Consistent with this speculation, inhibition of NGF by treatment with tanezumab was recently shown to have high analgesic efficacy in OA knees compared with placebo [8]. In the present study, CGRP- and TRPV1-positive cells, which are localized in DRG neurons in monoiodoacetate- (MIA-) treated OA animals [35, 36], were increased in the DRG of STR/Ort compared to C57BL/6J mice, suggesting that the elevation of synovial NGF in STR/Ort mice contributes to peripheral sensitization. However, several studies have shown that human OA chondrocytes also produce NGF by inflammatory cytokines [37, 38].…”

Section: Discussionsupporting

confidence: 79%

Nerve Growth Factor Regulation by TNF-αand IL-1βin Synovial Macrophages and Fibroblasts in Osteoarthritic Mice

Takano

Uchida

Miyagi

et al. 2016

Journal of Immunology Research

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To investigate the role of macrophages as a regulator and producer of nerve growth factor (NGF) in the synovial tissue (ST) of osteoarthritis (OA) joints, the gene expression profiles of several inflammatory cytokines in the ST, including synovial macrophages and fibroblasts, of OA mice (STR/Ort) were characterized. Specifically, real-time polymerase chain reaction analysis was used to evaluate the expression of tumor necrosis factor- (TNF-) α, interleukin- (IL-) 1β, IL-6, and NGF in CD11b+ and CD11b– cells isolated from the ST of a murine OA model. The effects of TNF-α, IL-1β, and IL-6 on the expression of NGF in cultured synovial cells were also examined. The expression of TNF-α, IL-1β, IL-6, and NGF in the ST of STR/Ort was higher than that in C57/BL6J mice. Compared to the CD11b– cell fraction, higher expression levels of TNF-α, IL-1β, and IL-6 were detected in the CD11b+ cell fraction, whereas no differences in the expression of NGF were detected between the two cell fractions. Notably, TNF-α upregulated NGF expression in synovial fibroblasts and macrophages and IL-1β upregulated NGF expression in synovial fibroblasts. IL-1β and TNF-α may regulate NGF signaling in OA joints and be suitable therapeutic targets for treating OA pain.

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Section: Discussionsupporting

confidence: 79%

Nerve Growth Factor Regulation by TNF-αand IL-1βin Synovial Macrophages and Fibroblasts in Osteoarthritic Mice

Takano

Uchida

Miyagi

et al. 2016

Journal of Immunology Research

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“…(ii) TRPV1 is co-localized with CB1 and CB2 in cerebromicrovascular endothelial cells [62] and with CB1 in endothelial cells from mesenteric arteries of cirrhotic rats [63,64]; (iii) TRPV1 is co-localized with both CB1 and CB2 in mouse bone-marrowderived dendritic cells [65], and in human skeletal muscle cells [66], myometrial smooth muscle cells [67], osteoclasts [68], proximal tubular (HK2) cells of the kidney [69], keratinocytes [70,71], melanocytes [72] and dental pulp cells [73]; (iv) TRPV1 is co-localized only with CB1 in human sperm cells [74], and only with CB2 in synoviocytes from rats after intraarticular injection of mono-iodo-acetate, a model of osteoarthritis [75]. In view of the previously reported cross-talk between TRPV1 and CB1 receptors at the level of down-stream signalling events [76,77], these many examples of co-expression between the channel and one or both cannabinoid receptor sub-types offer the opportunity of widening further the range of pharmacological effects that endogenous mediators capable of activating both types of receptors may have, and, hence, the extent of 'plasticity' that their action can produce in a large variety of biological systems.…”

Section: Co-expression Of Cb1 or Cb2 Receptors And Trpv1 Channels In mentioning

confidence: 99%

Why do cannabinoid receptors have more than one endogenous ligand?

Marzo

Petrocellis

2012

Phil. Trans. R. Soc. B

249

176

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The endocannabinoid system was revealed following the understanding of the mechanism of action of marijuana's major psychotropic principle, D 9-tetrahydrocannabinol, and includes two G-proteincoupled receptors (GPCRs; the cannabinoid CB1 and CB2 receptors), their endogenous ligands (the endocannabinoids, the best studied of which are anandamide and 2-arachidonoylglycerol (2-AG)), and the proteins that regulate the levels and activity of these receptors and ligands. However, other minor lipid metabolites different from, but chemically similar to, anandamide and 2-AG have also been suggested to act as endocannabinoids. Thus, unlike most other GPCRs, cannabinoid receptors appear to have more than one endogenous agonist, and it has been often wondered what could be the physiological meaning of this peculiarity. In 1999, it was proposed that anandamide might also activate other targets, and in particular the transient receptor potential of vanilloid type-1 (TRPV1) channels. Over the last decade, this interaction has been shown to occur both in peripheral tissues and brain, during both physiological and pathological conditions. TRPV1 channels can be activated also by another less abundant endocannabinoid, N-arachidonoyldopamine, but not by 2-AG, and have been proposed by some authors to act as ionotropic endocannabinoid receptors. This article will discuss the latest discoveries on this subject, and discuss, among others, how anandamide and 2-AG differential actions at TRPV1 and cannabinoid receptors contribute to making this signalling system a versatile tool available to organisms to fine-tune homeostasis.

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“…In patients with osteoarthritis, TRPV1 is expressed on synovium, as well as synovial fibroblasts suggesting both a neuronal and a non-neuronal role of TRPV1 in this condition [9,40]. In rats, TRPV1 is expressed in DRG neurons and knee joint synoviocytes [41,42]. Additionally, in the mono-iodoacetate (MIA) model of osteoarthritis, joint afferents in the DRG, as determined by Fast Blue staining, expressed a greater amount of TRPV1 (72%) compared to normal joint afferents (54%) [40].…”

Section: Expression Changes In Trpv1 Channels In Chronic Pain Condmentioning

confidence: 99%

“… [74] mouseSTZSTZ has direct action on neurons, which up-regulates TRPV1 expression and increases capsaicin-induced currents [14] humanCPPTRPV1 expression was 7-fold higher in pelvic tissues from patients with CPP compared to controls, which was not due to an increase in neuronal fibers. [33] mousePSNLIn neonatal capsaicin-treated mice, TRPV1 expression is absent but increases in A-fiber DRG neurons after PSNL [46] humanOATRPV1 mRNA is increased 5-fold in osteoclasts from osteoporotic and osteoporotic women compared to normal menopausal women. Capsaicin was less potent and produced a decreased Ca 2+ response in osteoclasts from osteoporotic and osteoporotic women compared to normal menopausal women. [42] ratMIATRPV1 is expressed in DRG neurons and knee joint synovium of control and MIA-treated rats. No quantitative differences between groups evaluated. [13] humanGERDTRPV1 mRNA and protein were significantly increased in patients with erosive esophagitis compared to asymptomatic and healthy control patients. [35] mouseSNLInjury increased the percentage of heat sensitive small-diameter IB4 positive isolated DRG neurons (13% control vs. 56% SNL) and conversely decreased the percentage of heat sensitive small-diameter IB4 negative isolated DRG neurons (66% control vs. 34% SNL).…”

Section: Tablementioning

confidence: 99%

TRPV1 Antagonists and Chronic Pain: Beyond Thermal Perception

Brandt

Beyer²,

Stahl

2012

Pharmaceuticals

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Abstract:In the last decade, considerable evidence as accumulated to support the development of Transient Receptor Potential Vanilloid 1 (TRPV1) antagonists for the treatment of various chronic pain conditions. Whereas there is a widely accepted rationale for the development of TRPV1 antagonists for the treatment of various inflammatory pain conditions, their development for indications of chronic pain, where conditions of tactical, mechanical and spontaneous pain predominate, is less clear. Preclinical localization and expression studies provide a firm foundation for the use of molecules targeting TRPV1 for conditions of bone pain, osteoarthritis and neuropathic pain. Selective TRPV1 antagonists weakly attenuate tactile and mechanical hypersensivity and are partially effective for behavioral and electrophysiological endpoints that incorporate aspects of spontaneous pain. While initial studies with TRPV1 antagonist in normal human subjects indicate a loss of warm thermal perception, clinical studies assessing allelic variants suggests that TRPV1 may mediate other sensory modalities under certain conditions. The focus of this review is to summarize the current perspectives of TRPV1 for the treatment of conditions beyond those with a primary thermal sensitivity. OPEN ACCESSPharmaceuticals 2012, 5 115

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Paradoxical effects of the cannabinoid CB2 receptor agonist GW405833 on rat osteoarthritic knee joint pain

Abstract: These data indicate that GW405833 reduces the mechanosensitivity of afferent nerve fibres in control joints but causes nociceptive responses in OA joints. The observed pro-nociceptive effect of GW405833 appears to involve TRPV1 receptors.

Cited by 70 publications

References 47 publications

Nerve Growth Factor Regulation by TNF-αand IL-1βin Synovial Macrophages and Fibroblasts in Osteoarthritic Mice

Nerve Growth Factor Regulation by TNF-αand IL-1βin Synovial Macrophages and Fibroblasts in Osteoarthritic Mice

Why do cannabinoid receptors have more than one endogenous ligand?

TRPV1 Antagonists and Chronic Pain: Beyond Thermal Perception

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