Cortisol-mediated adhesion of synovial fibroblasts is dependent on the degradation of anandamide and activation of the endocannabinoid system
In rheumatoid arthritis (RA) synovial fluid, levels of the endocannabinoids anandamide (AEA) and 2-arachidonylglycerol are elevated. Since synovial fibroblasts (SFs) possess all of the enzymes necessary for endocannabinoid synthesis, it is likely that these cells contribute significantly to elevated endocannabinoid levels. While glucocorticoids initiate endocannabinoid synthesis in neurons, this study was undertaken to test whether cortisol also regulates endocannabinoid levels in mesenchymal cells such as SFs, and whether this interferes with integrin-mediated adhesion.
Lowin, T., Zhu, W., Dettmer-Wilde, K. and Straub, R. H. (2012), Cortisol-mediated adhesion of synovial fibroblasts is dependent on the degradation of anandamide and activation of the endocannabinoid system. Arthritis & Rheumatism, 64: 3867–3876. doi: 10.1002/art.37684
Lack of effect of chronic pre-treatment with the FAAH inhibitor URB597 on inflammatory pain behaviour: evidence for plastic changes in the endocannabinoid system.
Elevating levels of endocannabinoids with inhibitors of fatty acid amide hydrolase (FAAH) is a major focus of pain research, purported to be a safer approach devoid of cannabinoid receptor-mediated side effects. Here, we have determined the effects of sustained pharmacological inhibition of FAAH on inflammatory pain behaviour and if pharmacological inhibition of FAAH was as effective as genetic deletion of FAAH on pain behaviour.
Okine BN, Norris LM, Woodhams S, et al. Lack of effect of chronic pre-treatment with the FAAH inhibitor URB597 on inflammatory pain behaviour: evidence for plastic changes in the endocannabinoid system. British Journal of Pharmacology 2012;167(3):627-640. doi:10.1111/j.1476-5381.2012.02028.x.
Cannabinoids: novel therapies for arthritis?
A key feature of osteoarthritis and rheumatoid arthritis is the loss of articular cartilage. Cartilage breakdown is mediated by complex interactions of proinflammatory cytokines, such as IL-1, inflammatory mediators, including nitric oxide and prostaglandin E(2), and proteases, including matrix metalloproteinases and aggrecanases, such as ADAMTS-4 and -5. Cannabinoids have been shown to reduce joint damage in animal models of arthritis. They have also been shown to prevent IL-1-induced matrix breakdown of collagen and proteoglycan, indicating that cannabinoids may mediate chondroprotective effects. Cannabinoids produce their effects via several cannabinoid receptors and it is important to identify the key cannabinoids and their receptors that are involved in chondroprotection. This review aims to outline the current and future prospects of cannabinoids as anti-arthritic therapeutics, in terms of their ability to prevent cartilage breakdown.
Robert I Scheinman. (2012) Rheumatology Mini Focus. Future Medicinal Chemistry 4:6, 697-699. Online publication date: 1-Apr-2012.
Fatty acid amide hydrolase blockade attenuates the development of collagen-induced arthritis and related thermal hyperalgesia in mice.
Fatty acid amide hydrolase (FAAH) is the primary degradative enzyme of the endocannabinoid anandamide (N-arachidonoylethanolamine), which activates cannabinoid CB(1) and CB(2) receptors. FAAH disruption reduces nociception in a variety of acute rodent models of inflammatory pain. The present study investigated whether these actions extend to the chronic, collagen-induced arthritis (CIA) model. We investigated the anti-arthritic and anti-hyperalgesic effects of genetic deletion or pharmacological inhibition of FAAH in the CIA model. FAAH (-/-) mice, and FAAH-NS mice that express FAAH exclusively in nervous tissue, displayed decreased severity of CIA and associated hyperalgesia. These phenotypic anti-arthritic effects were prevented by repeated daily injections of the CB(2) receptor antagonist, SR144528, but not the CB(1) receptor antagonist rimonabant. Similarly, repeated administration of the FAAH inhibitor URB597 reduced CIA severity, and acute administration of rimonabant, but not SR144528, blocked the anti-hyperalgesic effects of prolonged FAAH inhibition, suggesting that prolonged CB(2) receptor activation reduces the severity of CIA, whereas acute CB(1) receptor activation reduces CIA-induced hyperalgesia. In contrast, acute administration of URB597 elicited a CB(1) receptor-dependent anti-hyperalgesic effect. The observed anti-arthritic and anti-hyperalgesic properties of FAAH inhibition, coupled with a lack of apparent behavioral alterations, suggest that endocannabinoid modulating enzymes offer a promising therapeutic target for the development of novel pharmacological approaches to treat rheumatoid arthritis and associated hyperalgesia.
Kinsey SG, Naidu PS, Cravatt BF, Dudley DT, Lichtman AH. Fatty acid amide hydrolase blockade attenuates the development of collagen-induced arthritis and related thermal hyperalgesia in mice. Pharmacology, biochemistry, and behavior 2011;99(4):718-725. doi:10.1016/j.pbb.2011.06.022.
Is lipid signaling through cannabinoid 2 receptors part of a protective system?
The mammalian body has a highly developed immune system which guards against continuous invading protein attacks and aims at preventing, attenuating or repairing the inflicted damage. It is conceivable that through evolution analogous biological protective systems have been evolved against non-protein attacks. There is emerging evidence that lipid endocannabinoid signaling through cannabinoid 2 (CB2) receptors may represent an example/part of such a protective system/armamentarium. Inflammation/tissue injury triggers rapid elevations in local endocannabinoid levels, which in turn regulate signaling responses in immune and other cells modulating their critical functions. Changes in endocannabinoid levels and/or CB2 receptor expressions have been reported in almost all diseases affecting humans, ranging from cardiovascular, gastrointestinal, liver, kidney, neurodegenerative, psychiatric, bone, skin, auto-immune, lung disorders to pain and cancer, and modulating CB2 receptor activity holds tremendous therapeutic potential in these pathologies. While CB2 receptor activation in general mediates immunosuppressive effects, which limit inflammation and associated tissue injury in large number of pathological conditions, in some disease states activation of the CB2 receptor may enhance or even trigger tissue damage, which will also be discussed alongside the protective actions of the CB2 receptor stimulation with endocannabinoids or synthetic agonists, and the possible biological mechanisms involved in these effects.
Pacher P, Mechoulam R. Is lipid signaling through cannabinoid 2 receptors part of a protective system? Progress in lipid research 2011;50(2):193-211. doi:10.1016/j.plipres.2011.01.001.
Full Text http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3062638/
Cannabinoids for treatment of chronic non-cancer pain; a systematic review of randomized trials.
Effective therapeutic options for patients living with chronic pain are limited. The pain relieving effect of cannabinoids remains unclear. A systematic review of randomized controlled trials (RCTs) examining cannabinoids in the treatment of chronic non-cancer pain was conducted according to the PRISMA statement update on the QUORUM guidelines for reporting systematic reviews that evaluate health care interventions. Cannabinoids studied included smoked cannabis, oromucosal extracts of cannabis based medicine, nabilone, dronabinol and a novel THC analogue. Chronic non-cancer pain conditions included neuropathic pain, fibromyalgia, rheumatoid arthritis, and mixed chronic pain. Overall the quality of trials was excellent. Fifteen of the eighteen trials that met the inclusion criteria demonstrated a significant analgesic effect of cannabinoid as compared with placebo and several reported significant improvements in sleep. There were no serious adverse effects. Adverse effects most commonly reported were generally well tolerated, mild to moderate in severity and led to withdrawal from the studies in only a few cases. Overall there is evidence that cannabinoids are safe and modestly effective in neuropathic pain with preliminary evidence of efficacy in fibromyalgia and rheumatoid arthritis. The context of the need for additional treatments for chronic pain is reviewed. Further large studies of longer duration examining specific cannabinoids in homogeneous populations are required.
Lynch ME, Campbell F. Cannabinoids for treatment of chronic non-cancer pain; a systematic review of randomized trials. British Journal of Clinical Pharmacology 2011;72(5):735-744. doi:10.1111/j.1365-2125.2011.03970.x.
Cannabidiol as an emergent therapeutic strategy for lessening the impact of inflammation on oxidative stress.
Oxidative stress with reactive oxygen species generation is a key weapon in the arsenal of the immune system for fighting invading pathogens and initiating tissue repair. If excessive or unresolved, however, immune-related oxidative stress can initiate further increasing levels of oxidative stress that cause organ damage and dysfunction. Targeting oxidative stress in various diseases therapeutically has proven more problematic than first anticipated given the complexities and perversity of both the underlying disease and the immune response. However, growing evidence suggests that the endocannabinoid system, which includes the CB₁ and CB₂ G-protein-coupled receptors and their endogenous lipid ligands, may be an area that is ripe for therapeutic exploitation. In this context, the related nonpsychotropic cannabinoid cannabidiol, which may interact with the endocannabinoid system but has actions that are distinct, offers promise as a prototype for anti-inflammatory drug development. This review discusses recent studies suggesting that cannabidiol may have utility in treating a number of human diseases and disorders now known to involve activation of the immune system and associated oxidative stress, as a contributor to their etiology and progression. These include rheumatoid arthritis, types 1 and 2 diabetes, atherosclerosis, Alzheimer disease, hypertension, the metabolic syndrome, ischemia-reperfusion injury, depression, and neuropathic pain.
Booz GW. Cannabidiol as an Emergent Therapeutic Strategy for Lessening the Impact of Inflammation on Oxidative Stress. Free radical biology & medicine2011;51(5):1054-1061. doi:10.1016/j.freeradbiomed.2011.01.007.
Full Text http://www.ncbi.nlm.nih.gov/pmc/articles/PMC308554
Cannabinoid-induced apoptosis in immune cells as a pathway to immunosuppression
Cannabinoids are a group of compounds present in Cannabis plant (Cannabis sativa L.). They mediate their physiological and behavioral effects by activating specific cannabinoid receptors. With the recent discovery of the cannabinoid receptors (CB1 and CB2) and the endocannabinoid system, research in this field has expanded exponentially. Cannabinoids have been shown to act as potent immunosuppressive and anti-inflammatory agents and have been shown to mediate beneficial effects in a wide range of immune-mediated diseases such as multiple sclerosis, diabetes, septic shock, rheumatoid arthritis, and allergic asthma. Cannabinoid receptor 1 (CB1) is mainly expressed on the cells of the central nervous system as well as in the periphery. In contrast, cannabinoid receptor 2 (CB2) is predominantly expressed on immune cells. The precise mechanisms through which cannabinoids mediate immunosuppression is only now beginning to be understood and can be broadly categorized into four pathways: apoptosis, inhibition of proliferation, suppression of cytokine and chemokine production and induction of T regulatory cells (T regs). Studies from our laboratory have focused on mechanisms of apoptosis induction by natural and synthetic cannabinoids through activation of CB2 receptors. In this review, we will focus on apoptotic mechanisms of immunosuppression mediated by cannabinoids on different immune cell populations and discuss how activation of CB2 provides a novel therapeutic modality against inflammatory and autoimmune diseases as well as malignancies of the immune system, without exerting the untoward psychotropic effects.
Rieder SA, Chauhan A, Singh U, Nagarkatti M, Nagarkatti P. Cannabinoid-induced apoptosis in immune cells as a pathway to immunosuppression.Immunobiology 2010;215(8):598-605. doi:10.1016/j.imbio.2009.04.001.
Tonic Modulation of Spinal Hyperexcitability by the Endocannabinoid Receptor System in a Rat Model of Osteoarthritis Pain
Our findings provide new evidence for altered spinal nociceptive processing indicative of central sensitization and for adaptive changes in the spinal cord endocannabinoid system in an experimental model of OA. The novel control of spinal cord neuronal responses by spinal cord CB2 receptors suggests that this receptor system may be an important target for the modulation of pain in OA.
Sagar DR, Staniaszek LE, Okine BN, et al. Tonic Modulation of Spinal Hyperexcitability by the Endocannabinoid Receptor System in a Rat Model of Osteoarthritis Pain. Arthritis and Rheumatism 2010;62(12):3666-3676. doi:10.1002/art.27698.
Paradoxical effects of the cannabinoid CB2 receptor agonist GW405833 on rat osteoarthritic knee joint pain.
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.
- Osteoarthritis Cartilage. 2010 Nov;18(11):1536-43. doi: 10.1016/j.joca.2010.09.005. Epub 2010 Sep 21.
† Department of Physiology & Pharmacology, University of Calgary, 3330 Hospital Drive NW Calgary, AB T2N 4N1, Canada
‡ Neuroscience Discovery, Eli Lilly and Company, Erl Wood ELCL, United Kingdom
§ Neuroscience Discovery, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA
- Full Text http://www.sciencedirect.com/science/article/pii/S1063458410003158
Cannabinoids as novel anti-inflammatory drugs
Cannabinoids are a group of compounds that mediate their effects through cannabinoid receptors. The discovery of Δ9-tetrahydrocannabinol (THC) as the major psychoactive principle in marijuana, as well as the identification of cannabinoid receptors and their endogenous ligands, has led to a significant growth in research aimed at understanding the physiological functions of cannabinoids. Cannabinoid receptors include CB1, which is predominantly expressed in the brain, and CB2, which is primarily found on the cells of the immune system. The fact that both CB1 and CB2 receptors have been found on immune cells suggests that cannabinoids play an important role in the regulation of the immune system. Recent studies demonstrated that administration of THC into mice triggered marked apoptosis in T cells and dendritic cells, resulting in immunosuppression. In addition, several studies showed that cannabinoids downregulate cytokine and chemokine production and, in some models, upregulate T-regulatory cells (Tregs) as a mechanism to suppress inflammatory responses. The endocannabinoid system is also involved in immunoregulation. For example, administration of endocannabinoids or use of inhibitors of enzymes that break down the endocannabinoids, led to immunosuppression and recovery from immune-mediated injury to organs such as the liver. Manipulation of endocannabinoids and/or use of exogenous cannabinoids in vivo can constitute a potent treatment modality against inflammatory disorders. This review will focus on the potential use of cannabinoids as a new class of anti-inflammatory agents against a number of inflammatory and autoimmune diseases that are primarily triggered by activated T cells or other cellular immune components.
Nagarkatti P, Pandey R, Rieder SA, Hegde VL, Nagarkatti M. Cannabinoids as novel anti-inflammatory drugs. Future medicinal chemistry 2009;1(7):1333-1349. doi:10.4155/fmc.09.93.
Characterisation of the cannabinoid receptor system in synovial tissue and fluid in patients with osteoarthritis and rheumatoid arthritis
Cannabis-based medicines have a number of therapeutic indications, including anti-inflammatory and analgesic effects. The endocannabinoid receptor system, including the cannabinoid receptor 1 (CB1) and receptor 2 (CB2) and the endocannabinoids, are implicated in a wide range of physiological and pathophysiological processes. Pre-clinical and clinical studies have demonstrated that cannabis-based drugs have therapeutic potential in inflammatory diseases, including rheumatoid arthritis (RA) and multiple sclerosis. The aim of this study was to determine whether the key elements of the endocannabinoid signalling system, which produces immunosuppression and analgesia, are expressed in the synovia of patients with osteoarthritis (OA) or RA.
Richardson D, Pearson RG, Kurian N, et al. Characterisation of the cannabinoid receptor system in synovial tissue and fluid in patients with osteoarthritis and rheumatoid arthritis. Arthritis Research & Therapy2008;10(2):R43. doi:10.1186/ar2401.
In vivo effects of CB2 receptor-selective cannabinoids on the vasculature of normal and arthritic rat knee joints
Cannabinoids (CBs) are known to be vasoactive and to regulate tissue inflammation. The present study examined the in vivo vasomotor effects of the CB2 receptor agonists JWH015 and JWH133 in rat knee joints. The effect of acute and chronic joint inflammation on CB2 receptor-mediated responses was also tested.
McDougall JJ, Yu V, Thomson J. In vivo effects of CB2 receptor-selective cannabinoids on the vasculature of normal and arthritic rat knee joints. British Journal of Pharmacology 2008;153(2):358-366. doi:10.1038/sj.bjp.0707565.