Can CBD Oil Treat Rheumatoid Arthritis Symptoms? Many more studies, especially on large numbers of human participants, are still needed to fully understand the effects of CBD oil and other cannabis-based CB2 also plays a role in your immune system. /rheumatology/kei; Cannabis and cannabinoids. depression, diabetes, rheumatoid arthritis, anxiety, and opioid withdrawal. CBD acts The endocannabinoid system's purpose is to respond to endogenous. CBD Oil for Rheumatoid Arthritis [Understanding Endocannabinoids]. image Jonathan Miller | Updated on January 08/ CBD Oil for Rheumatoid Arthritis.
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As a result, hyperpolarization of the presynaptic membrane occurs, modulating the release of neurotransmitter and thus synaptic transmission. CB1 receptor stimulation regulates the intensity and duration of synaptic transmission Similarly, in immune cells, CB2 activation has been shown to mediate an inhibitory effect on activation, cell motility and secretion of inflammatory mediators Overview of the endocannabinoid-mediated synaptic signaling.
Arthritic pain is both nociceptive, resulting from the irritation of sensory nociceptors responsible for the detection of potentially noxious stimuli, and neuropathic, resulting from a malfunction in the somatosensory nervous system Extensive innervation within the joint helps facilitate the sensation of pain in inflammatory joint conditions Under normal physiological conditions, joint nociceptors are localized within the articular structure of the joint.
Under inflammatory conditions, these silent nociceptors expand to adjacent tissues and function to propagate and amplify the sensation of pain 33 , 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 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 Despite this optimism, hesitation in clinical application is prevalent with extensive guidelines published in different countries 37 — In chronic pain states, central sensitization results in the reorganization of the spinal nociceptive circuitry through a localized up-regulation of CB1 and CB2 receptor expression along the pain nexus.
As a result, hypersensitivity manifests as both hyperalgesia and allodynia occurs, for which standard analgesic treatments are unsuccessful. In neuropathic settings, both the up-regulation of spinal CB2 receptors 29 , 40 and a greater effect of intrathecally administered cannabinoid CB2 agonists have been noted The functional importance of CB2 up-regulation in the integration and sensitization of OA pain has been demonstrated through the use of genetically modified mice In pain experiments, mechanical induced allodynia was suppressed in transgenic mice overexpressing CB2 in the CNS By contrast, no significant changes in pain responses were observed in CB1 knockout mice, suggesting that the centrally controlled mechanisms of these nociceptive responses are primarily regulated via CB2, with minor input via CB1 The tonic release of spinal endocannabinoid levels counteract peripheral sensitization through enhanced endocannabinoid signaling within the spinal cord In a rat model of OA pain, systemic administration of CB2 agonist, JWH, suppressed pain behavior, while acute administration to the spine inhibited mechanically stimulated noxious neurotransmission More recently, an increased expression of CB1 accompanied by OA development has been demonstrated CB1 receptors are located on peripheral sympathetic nerve terminals as well as on nociceptive nerve fibers, where they modulate adrenergic signaling to influence cytokine production Stimulation of CB1 receptors desensitize neurons by modulating ion channels of the Transient receptor potentials TRP , suppressing action potentials and reducing pain.
Externally administered AEA and CB1 agonist, arachidonylchloroethylamide ACEA , have been shown to significantly reduce the firing rate of afferent nerve fibers in OA joints, but not in the control joints, suggesting a tonic release of endocannabinoids at the joint level in OA. Considering the close positioning of transient receptor potentials type 1 TRPV1 and CB1 receptors in relation to nociceptive transmission both have drawn interest in the development of novel therapies of OA pain and is discussed in more detail below 3 , 9.
TRP channels, also known as capsaicin receptors, are a group of ligand-gated ion channels responsible for the detection and integration of noxious stimuli 14 , Primarily found in the nociceptive neurons of the peripheral nervous system, stimulation of the transient receptor potential vanilloid receptor type 1 TRPV1 results in a cation influx and the production of an action potential that consequently results in the sensation of pain. As such, the TRPV1 channels represent a prime focus for the development of novel analgesics.
Indeed, it has been well-documented that heavy capsaicin dosing depletes neuropeptides levels, with a resultant suppression in the severity of adjuvant-induced joint disease Other antagonists that block TRPV1 activity capsazepine, ruthenium red as well as clinical trial compounds AMG, GRC, NGD have also been shown to be effective in reducing pain but have not progressed in development due to undesirable side effect levels of hyperthermia. In arthritis, TRPV1 receptors are located on peripheral cells and sensory neurons abundantly expressed in arthritic synovial tissue.
In addition to enhanced neurotransmitter release, stimulation of TRPV1 is associated with increases in inflammatory mediators contributing to joint inflammation Together, these findings indicate a novel link between TRP channels and cytokines in the generation of joint pain through central sensitization AEA is believed to modulate synaptic plasticity, a key component in arthritic pain, through actions at both the pre and postsynaptic TRPV1 channels On exposure, the TRPV1 channels are rapidly desensitized, resulting in reduced calcium influx and increased pain thresholds.
Additionally, cross-talk between CB1 and TRPV1 co-expressed on sensory nerves, modulate pain and inflammation in arthritis When co-expressed, CB1 agonists suppressed TRPV1 activation through dephosphorylation, increasing the threshold level for agonists Pharmacological elevations of AEA in an arthritic rat were shown to suppress hypersensitivity of afferent nociceptors and elevated pain thresholds by a process containing CB1 and TRPV1 channels This mechanism was confirmed through the use of joint blood flow experiments, which demonstrated that the vasomotor effects of a CB1 agonist in rat knees could be inhibited by TRPV1 antagonism Similarly, in a model of OA pain, local administration of CB1 agonist ACEA reduced mechanosensitivity of afferent nerve fibers, suppressing nociceptive transmission in OA and healthy rat knee joints.
More recently, the transient receptor potential canonical 5 TRPC5 expressed on fibroblast like synoviocytes cells within the joint has been shown to protect against pain and inflammation in arthritic mice Inhibition of TRPC5 using knockouts or pharmacological agents is correlated well with the propagation of joint inflammation and hyperalgesia, providing evidence that TRCP5 is a negative regulator of inflammation.
The proposed mechanism of action suggested by Alawi et al. These exciting results highlight how TRP receptors protect against pain and vascular joint inflammation in arthritis. There is increasing and exciting evidence showing that endocannabinoids regulate the immune response at both the innate monocytes, macrophages, neutrophils, NK cells, eosinophils, basophils, mast cells and adaptive immune level Immune cells are not only able to be influenced, but are also able to generate and secrete endocannabinoids that lead to changes in immune-cell behavior as well as the production of other inflammatory factors that subsequently influence tissue inflammation 56 , These anti-inflammatory effects may be due to direct action on participating immune cells, or by changes in the local endocannabinoid concentrations that then carry out anti-inflammatory actions.
In arthritis, persistent inflammation results in the infiltration of immune cells and the subsequent development of hypersensitivity. In an elegant study by Sancho et al. The protective effects of endocannabinoids have been noted in other inflammatory conditions such as multiple sclerosis , celiac disease, and periodontitis The anti-inflammatory potential of CB2 has been confirmed in mouse models of arthritis 61 , The protective CB2 effects include the suppression of pro-inflammatory cytokine and damaging proteinases secretion; as well as regulating immune cell adhesion and migration to the inflamed joint.
Together, this helps slow the perpetuation of disease and alleviate associated arthritic pain primarily derived from localized inflammation Further to this, elevated levels AEA and 2-AG are detected in the synovial fluid of RA and OA patients, but absent in healthy controls, suggest that local endocannabinoid secretion may assist in minimising inflammation in the arthritic joints 4, With both cannabinoid receptors and endogenous ligands present in inflamed human joints, targeting this system may hold therapeutic promise for both inflammatory, as well as degenerative arthritis Administration of cannabinoid agonists, WIN and CP, have shown the ability to reduce inflammatory IL-6 and interleukin-8 IL-8 cytokine production by fibroblast like synoviocytes cells, ameliorating acute inflammation and associated pain in arthritic joints 2 , Similarly, systemic administration of the CB2 agonist, JWH, suppressed pain and corrected deviation in circulating pro- and anti-inflammatory cytokines in the rat MIA model 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 In-vivo studies by Krustev et al.
In a similar study, URB suppressed inflammatory hyperemia in a mouse model of acute arthritis In the periphery, FAAH inhibition mediates anti-inflammatory effects by down regulating cytokine production and the desensitization of TRPV1, resulting in analgesia Inhibition of AEA catabolism is said to have promising effects in the management of OA pain mediated by both anti-inflammatory 65 and anti-hyperalgesia actions Therapeutic intervention in peripherally restricted CB1 antagonist and FAAH inhibition are promising strategies to ameliorate chronic inflammation and pain in RA.
In neurogenic inflammation, local afferent neurons secrete inflammatory mediators such as neurokinin A, substance P SP , and calcitonin gene-related peptide which perpetuate inflammation.
Once these neuropeptides are secreted, they act on adjacent mast cells to release histamine, which in turn evoke the release of SP and calcitonin gene-related peptide creating a positive feedback loop which amplifies the inflammatory response. These neuropeptides sensitize local articular afferents in the inflamed joint and stimulate the increases in TRPV1 expression, sustaining nociceptive signaling and the maintenance of neuropathic pain 43 , In RA, enhanced levels of nerve growth factor, prostaglandins and bradykinins within the synovium sensitize TRPV1 to the inflammatory stimuli and aggravate pain In RA, sustained stimulation of the sympathetic nervous system propagate inflammation through norepinephrine signaling.
The influence of adrenergic signaling and the loss of sympathetic nerve fibers in the inflamed tissue in RA has been demonstrated in several animal models of arthritis Sympathectomy in the early phase of the disease has been shown to ameliorate experimental arthritis, indicating the pro-inflammatory influence of adrenergic signaling During arthritic inflammation, nerve repulsion factors released by macrophages result in the withdrawal of sympathetic neurons from the synovial tissue and the subsequent depletion of synovial norepinephrine concentrations Peripheral norepinephrine release from the sympathetic terminals is regulated through the CB1 receptors and can be stimulated by respective CB1 endocannabinoid agonists such as AEA and 2-AG.
Recent research using CB1 knockout mice showed impaired neurogenesis when compared to wild type, suggesting endogenous CB1 signaling may promote basal levels of neurogenesis 73 , While further studies are required, this possible application to sympathetic nerves may promote the extension of nerves previously lost from the synovial space during arthritic inflammation 68 , As discussed above, neural circuits can modulate immune responses by secreting compounds that influence cell function or through the detection of inflammatory mediators, which in turn causes the nerves to relay signals or release immunomodulatory peptides back to the immune system.
The release of IL-1 following inflammation, for instance, act on the hypothalamic-pituitary adrenal axis via neuronal input to release glucocorticoids that then influence the peripheral immune response outcome. Such neural-immune reflex circuits that regulate innate immunity are well understood. Other neural-immune reflexes such as dopamine and electro-acupuncture based circuits also exist but are less-well defined, as shown in Figure 4 The effects of acupuncture stimulation on neural reflex immunity circuits provides important and exciting insights into the regulation of innate immunity and the discovery of new targets as anti-inflammatory therapeutics Neural reflex immunity circuits.
Various stimuli such as a inflammatory e. The generated efferent signals work to dampen the innate immune responses signaling through a efferent neurons of the hypothalamic-pituitary adrenal HPA axis, c via the release of dopamine via the adrenal medulla, or b via the local axon-axon reflex which suppress the innate immune responses by cytokine release and immune cell activation. Efferent signals sent via the sympathetic system d or vagus nerve e , release neurotransmitters that influence the immune response In this review, we have focused on the basic sciences of endocannabinoids and overviewed their role in inflammation and pain.
While compelling evidence suggests the therapeutic potential of endocannabinoids therapy in arthritis and chronic musculoskeletal pain syndromes, barriers to research include insufficient legally registered marijuana manufacturers and a limited number of clinical trials.
In the study by Blake et al. Treatment took place over a 5-week period in a randomized, double-blinded trial group of 58 RA patients. Although adverse events in the active treatment group were not serious, they were common In a separate review of cannabinoid-based therapies in chronic pain conditions, three of which were rheumatic pain 2 fibromyalgia, 1 RA , concluded that while the majority demonstrated improvements in pain, no direct evidence on effects of herbal marijuana in rheumatic pain The FAAH inhibitor, PF, showed both analgesic and anti-inflammatory effects in animal studies comparable to naproxen However, when compared to naproxen, PF was ineffective for OA pain when compared to placebo-control in a randomized phase II clinical trial Also interesting and worth mentioning is the relationship between cyclooxygenase enzyme COX inhibitors and endocannabinoids.
COX enzyme is involved in the generation of prostaglandins from arachidonic acid that mediates inflammation. What is less well appreciated is that COX enzyme also metabolizes endocannabinoids to prostaglandin-glycerol esters for 2-AG and prostaglandin ethanolamines for AEA, as shown in Figure 2. These bioactive lipids may have a role in inflammation What is also not known is the functional consequences between cyclooxygenase-2 COX-2 inhibition and endocannabinoid effects.
More recently, focus has been drawn to dual-acting compounds such as OMDM In an MIA rat model of OA, OMDM exhibited a meaningful reversal of hypersensitivity in joint pain, representing a promising avenue in endocannabinoid pain management.
While the benefits of pharmaceutically prepared cannabinoid treatments have been inconsistent with large variations between species and population groups, they appear to have clinical benefits warranting the need for further investigation. Comprehensive evaluations through well-controlled randomized trials are also required to clarify the true clinical efficacy and long-term risks associated with cannabinoid therapy.
Advancements in our understanding of the endocannabinoid system and cannabinoid pharmacology, has raised the hope of exciting new pharmacological entities. Cannabis-based medications which enhance endocannabinoid function may represent a novel therapeutic solution to disorders associated with chronic pain and remains a promising avenue of contemporary importance.
No conflict of interest was declared by the authors. The authors declared that this study has received no financial support. National Center for Biotechnology Information , U. Journal List Eur J Rheumatol v. Published online Sep 1. Nicola Barrie and Nicholas Manolios. Author information Article notes Copyright and License information Disclaimer.
Received Feb 10; Accepted Apr This article has been cited by other articles in PMC. Abstract Pain is the most common manifestation of both acute and chronic inflammation that often challenges patients with rheumatic disease. Endocannabinoids, pain, inflammation, arthritis. The Endocannabinoid System Since the identification of endocannabinoid receptors, the potential of cannabinoid pharmacotherapy in clinical pain conditions has received much attention 1 , 2.
Endocannabinoid Synthesis and Degradation While the predominant endocannabinoids AEA and 2-AG are both lipid molecules generated from the breakdown of arachidonic acid, they share very few similarities in their biosynthetic pathways, as shown in Figure 1 Open in a separate window.
The inactivation of endocannabinoids FAAH: Endocannabinoid Receptors Various inhibition studies of the cannabinoid receptors have shown that endocannabinoids attenuate and suppress the perception of pain Cannabinoid receptor 1 Cannabinoid receptor 1 is the principal receptor of the central nervous system CNS and is densely expressed in several areas of the brain and supraspinal regions involved with nociceptive transmission.
Cannabinoid Receptor 2 In the periphery, CB2 receptors are widely located on immune cells and therefore represent a target for influencing inflammatory pain processing. Intracellular Endocannabinoid Signaling Cannabinoid receptors located on the presynaptic neurons regulate the synthesis and secretion of neurotransmitters to the synapse, as shown in Figure 3 Endocannabinoids and Arthritic Pain Arthritic pain is both nociceptive, resulting from the irritation of sensory nociceptors responsible for the detection of potentially noxious stimuli, and neuropathic, resulting from a malfunction in the somatosensory nervous system Changes in CB Receptor Expression In chronic pain states, central sensitization results in the reorganization of the spinal nociceptive circuitry through a localized up-regulation of CB1 and CB2 receptor expression along the pain nexus.
Changes in TRP Stimulation TRP channels, also known as capsaicin receptors, are a group of ligand-gated ion channels responsible for the detection and integration of noxious stimuli 14 , Endocannabinoids and Inflammation There is increasing and exciting evidence showing that endocannabinoids regulate the immune response at both the innate monocytes, macrophages, neutrophils, NK cells, eosinophils, basophils, mast cells and adaptive immune level Neurogenic Inflammation In neurogenic inflammation, local afferent neurons secrete inflammatory mediators such as neurokinin A, substance P SP , and calcitonin gene-related peptide which perpetuate inflammation.
Neural-immune Circuits in Inflammation In RA, sustained stimulation of the sympathetic nervous system propagate inflammation through norepinephrine signaling. Current Work and Future Direction of Research In this review, we have focused on the basic sciences of endocannabinoids and overviewed their role in inflammation and pain. A random walk through a cannabis field. History of cannabis and its preparations in saga, science, and sobriquet.
Spinal and peripheral mechanisms of cannabinoid antinociception: Endocannabinoids in pain modulation. Prostaglandins Leukot Essent Fatty Acids. And lastly, CBD oil is a well-known and very well-documented anti-inflammatory, so the majority of RA sufferers can expect to find significant joint pain relief when taking the medication, regardless of whatever internal mechanisms the cannabinoid may have on T-cells or the immune response.
A lot of people like to use topical CBD oils, creams, and salves as rheumatoid arthritis treatment. These medications are fast-acting, and incredibly simple to use. All you do is massage the ointment into the affected area, and the active CBD compound is absorbed into the tissue where it begins interacting with receptors of the ECS.
Likewise, oral CBD tinctures are also effective at treating rheumatoid arthritis. These oils usually come in a dropper or spray bottle, and are administered sublingually under the tongue.
Absorptive tissues work to absorb the active CBD compounds, at which point they enter into the bloodstream and travel to the site of inflammation. This type of CBD oil usually takes longer to begin working, but patients can expect the effects and therapeutic relief to be longer-lasting than topical creams or ointments. If you are looking for some great brands that develop excellent CBD oils and creams, check out our homepage. Each brand has been rated by price, quality and purity.
Jonathan Miller, age 53 is an Ex Railyard Engineer who suffers from chronic back pain and anxiety. Other risk factors associated with rheumatoid arthritis include: Sex women are statistically three times more likely to develop the condition than men Genes there is definitely a genetic factor associated with onset RA, though scientists are unclear what gene s are specifically involved Obesity obese individuals are statistically proven to have significantly slowed metabolisms, which can promote inflammation of joint tissue, including tissues of the synovial membrane Also, rheumatoid factor is a specific antigen that has been recognized and associated with onset RA, though doctors and researchers are still unclear what exactly it does in terms of instigating immune cells to attack healthy joint tissue.
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The endocannabinoid system in pain and inflammation: Its relevance to rheumatic disease
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