Endogenous systems involved in exercise-induced analgesia.

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“Exercise-induced analgesia is a phenomenon discussed worldwide. This effect began to be investigated in the early 1970s in healthy individuals and rodents during and after an acute or chronic session of running or swimming. Thereafter, studies found this effect was also induced by resistance exercises. Over the years, many studies have demonstrated the importance of exercise-induced analgesia in relieving pain caused by different conditions, such as fibromyalgia, low back pain, neuropathy, and osteoarthritis. This review aims to provide the reader with an in-depth description of the main endogenous systems, substances, neurotransmitters, receptors and enzymes that are thought to be involved in the analgesic effect induced by exercise. Many hypotheses have been proposed to elucidate the mechanisms responsible for exercise-induced analgesia. One of the most accepted hypotheses has been the activation of several endogenous systems described as analgesics. Studies have demonstrated that during and after exercise different endogenous systems are activated, which release substances or neurotransmitters, such as opioids, nitric oxide, serotonin, catecholamines and endocannabinoids, that may modulate the pain perception.”  https://www.ncbi.nlm.nih.gov/pubmed/29769416

http://www.jpp.krakow.pl/journal/archive/02_18/pdf/jpp.2018.1.01.pdf

“Exercise activates the endocannabinoid system.”  https://www.ncbi.nlm.nih.gov/pubmed/14625449

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Cannabis and joints: scientific evidence for the alleviation of osteoarthritis pain by cannabinoids.

 

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“Cannabis has been used for millennia to treat a multitude of medical conditions including chronic pain.

Osteoarthritis (OA) pain is one of the most common types of pain and patients often turn to medical cannabis to manage their symptoms.

While the majority of these reports are anecdotal, there is a growing body of scientific evidence which supports the analgesic potential of cannabinoids to treat OA pain.

OA pain manifests as a combination of inflammatory, nociceptive, and neuropathic pain, each requiring modality-specific analgesics. The body’s innate endocannabinoid system (ECS) has been shown to ameliorate all of these pain subtypes.

This review summarizes the components of the ECS and details the latest research pertaining to plant-based and man-made cannabinoids for the treatment of OA pain. Recent pre-clinical evidence supporting a role for the ECS to control OA pain is described as well as current clinical evidence of the efficacy of cannabinoids for treating OA pain in mixed patient populations.

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Joint problems arising from lack of repair mechanisms: can cannabinoids help?

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“Osteoarthritis (OA) is the most common disease of joints, which are complex organs where cartilage, bone and synovium cooperate to allow the range of movements. During the disease progression, the function of all three main components is jeopardized. Nevertheless, the involvement of each tissue in OA development is still not established and is the topic of the present review. The available OA therapies are symptomatic, largely targeting pain management rather than disease progression. The strong need to develop a treatment for cartilage degeneration, bone deformation and synovial inflammation has led to research on the involvement of the endocannabinoid system in the development of OA. The current review discusses the research on this topic to date and notes the advantages of exploiting endocannabinoid system modulation for cartilage, bone and synovium homeostasis, which could prevent the further progression of OA.”

https://www.ncbi.nlm.nih.gov/pubmed/29574720

https://bpspubs.onlinelibrary.wiley.com/doi/abs/10.1111/bph.14204

“We provide experimental evidence to show that activation of the cannabinoid system enhances the survival, migration and chondrogenic differentiation of MSCs, which are three major tenets behind the success of a cell-based tissue-engineered cartilage repair strategy. These findings highlight the potential for cannabinoids to provide a dual function by acting as anti-inflammatory agents as well as regulators of MSC biology in order to enhance tissue engineering strategies aimed at cartilage repair.”

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Characterization of endocannabinoids and related acylethanolamides in the synovial fluid of dogs with osteoarthritis: a pilot study.

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“Cannabis-based drugs have been shown to be effective in inflammatory diseases.

A number of endocannabinoids including N- arachidonoylethanolamide (anandamide, AEA) and 2-arachidonyl glycerol (2-AG) with activity at the cannabinoidreceptors (CBR) CBR1 and CBR2, have been identified. Other structurally related endogenous fatty acid compounds such as oleoylethanolamide (OEA) and palmitoyl ethanolamide (PEA) have been identified in biological tissues.

These compounds do not bind to CBR but might be involved in facilitating the actions of directly acting endocannabinoids and thus are commonly termed “entourage” compounds due to their ability to modulate the endocannabinoid system.

The aim of this study was to evaluate the presence of endocannabinoids and entourage compounds in the synovial fluid of dogs with osteoarthritis subjected to arthrotomy of the knee joint. Cytokines and cytology were studied as well.

AEA, 2-AG, OEA and PEA were all present in the synovial fluid of arthritic knees and in the contralateral joints; in addition, a significant increase of OEA and 2AG levels were noted in SF from OA knees when compared to the contralateral joints.

The identification and quantification of endocannabinoids and entourage compounds levels in synovial fluids from dogs with OA of the knee is reported for the first time. Our data are instrumental for future studies involving a greater number of dogs. Cannabinoids represent an emerging and innovative pharmacological tool for the treatment of OA and further studies are warranted to evaluate the effectiveness of cannabinoids in veterinary medicine.”

https://www.ncbi.nlm.nih.gov/pubmed/29110674

“The ECS can be exploited as a potential therapeutic option for OA. We have demonstrated the presence of AEA, 2-AG, OEA and PEA in the SF of dogs with OA. Our data open the avenue to future studies involving a higher number of dogs and aimed at defining the role played by these compounds in OA of the dogs. Both plant-derived and synthetic agonists of CBRs represent an emerging and innovative pharmacological tool for the treatment of OA. ” https://bmcvetres.biomedcentral.com/articles/10.1186/s12917-017-1245-7

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Is cannabis an effective treatment for joint pain?

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“Cannabis has been used to treat pain for thousands of years.

However, since the early part of the 20th century, laws restricting cannabis use have limited its evaluation using modern scientific criteria. Over the last decade, the situation has started to change because of the increased availability of cannabis in the United States for either medical or recreational purposes, making it important to provide the public with accurate information as to the effectiveness of the drug for joint pain among other indications.

The major psychotropic component of cannabis is Δ9-tetrahydrocannabinol (THC), one of some 120 naturally occurring phytocannabinoids. Cannabidiol (CBD) is another molecule found in herbal cannabis in large amounts. Although CBD does not produce psychotropic effects, it has been shown to produce a variety of pharmacological effects. Hence, the overall effects of herbal cannabis represent the collective activity of THC, CBD and a number of minor components.

The action of THC is mediated by two major G-protein coupled receptors, cannabinoid receptor type 1 (CB1) and CB2, and recent work has suggested that other targets may also exist. Arachidonic acid derived endocannabinoids are the normal physiological activators of the two cannabinoid receptors.

Natural phytocannabinoids and synthetic derivatives have produced clear activity in a variety of models of joint pain in animals. These effects are the result of both inhibition of pain pathway signalling (mostly CB1) and anti-inflammatory effects (mostly CB2). There are also numerous anecdotal reports of the effectiveness of smoking cannabis for joint pain.

Indeed, it is the largest medical request for the use of the drug. However, these reports generally do not extend to regulated clinical trials for rheumatic diseases. Nevertheless, the preclinical and human data that do exist indicate that the use of cannabis should be taken seriously as a potential treatment of joint pain.”

https://www.ncbi.nlm.nih.gov/pubmed/28967368

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Attenuation of early phase inflammation by cannabidiol prevents pain and nerve damage in rat osteoarthritis.

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“Osteoarthritis (OA) is a multifactorial joint disease, which includes joint degeneration, intermittent inflammation, and peripheral neuropathy. Cannabidiol (CBD) is a non-euphoria producing constituent of cannabis that has the potential to relieve pain.

The aim of this study was to determine if CBD is anti-nociceptive in OA, and whether inhibition of inflammation by CBD could prevent the development of OA pain and joint neuropathy.

The therapeutic and prophylactic effects of peripheral CBD (100-300μg) were assessed. In end stage OA, CBD dose-dependently decreased joint afferent firing rate, and increased withdrawal threshold and weight bearing (p<0.0001; n=8). Acute, transient joint inflammation was reduced by local CBD treatment (p<0.0001; n=6). Prophylactic administration of CBD prevented the development of MIA-induced joint pain at later time points (p<0.0001; n=8), and was also found to be neuroprotective (p<0.05; n=6-8).

The data presented here indicate that local administration of CBD blocked OA pain. Prophylactic CBD treatment prevented the later development of pain and nerve damage in these OA joints.

These findings suggest that CBD may be a safe, useful therapeutic for treating OA joint neuropathic pain.”

https://www.ncbi.nlm.nih.gov/pubmed/28885454             https://insights.ovid.com/crossref?an=00006396-900000000-99152

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Tissue Engineering of Cartilage; Can Cannabinoids Help?

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“This review discusses the role of the cannabinoid system in cartilage tissue and endeavors to establish if targeting the cannabinoid system has potential in mesenchymal stem cell based tissue-engineered cartilage repair strategies.

The review discusses the potential of cannabinoids to protect against the degradation of cartilage in inflamed arthritic joints and the influence of cannabinoids on the chondrocyte precursors, mesenchymal stem cells (MSCs).

We provide experimental evidence to show that activation of the cannabinoid system enhances the survival, migration and chondrogenic differentiation of MSCs, which are three major tenets behind the success of a cell-based tissue-engineered cartilage repair strategy.

These findings highlight the potential for cannabinoids to provide a dual function by acting as anti-inflammatory agents as well as regulators of MSC biology in order to enhance tissue engineering strategies aimed at cartilage repair.”

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High-Intensity Swimming Exercise Decreases Glutamate-Induced Nociception by Activation of G-Protein-Coupled Receptors Inhibiting Phosphorylated Protein Kinase A.

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“Several studies in humans have reported that improved pain control is associated with exercise in a variety of painful conditions, including osteoarthritis, fibromyalgia, and neuropathic pain.

Despite the growing amount of experimental data on physical exercise and nociception, the precise mechanisms through which high-intensity exercise reduces pain remain elusive.

Since the glutamatergic system plays a major role in pain transmission, we firstly analyzed if physical exercise could be able to decrease glutamate-induced nociception through G-protein-coupled receptor (G-PCR) activation.

The second purpose of this study was to examine the effect of exercising upon phosphorylation of protein kinase A (PKA) isoforms induced by intraplantar (i.pl.) glutamate injection in mice.

Our results demonstrate that high-intensity swimming exercise decreases nociception induced by glutamate and that i.pl. or intrathecal injections of cannabinoid, opioid, and adenosine receptor antagonists, AM281, naloxone, and 1,3-dipropyl-8-cyclopentylxanthine (DPCPX), respectively, prevent this effect.

Furthermore, the peripheral A1 and opioid receptors, but not CB1, are also involved in exercise’s effect. We also verified that glutamate injection increases levels of phosphorylated PKA (p-PKA). High-intensity swimming exercise significantly prevented p-PKA increase.

The current data show the direct involvement of the glutamatergic system on the hyponociceptive effect of high-intensity swimming exercise as well as demonstrate that physical exercise can activate multiple intracellular pathways through G-PCR activation, which share the same endogenous mechanism, i.e., inhibition of p-PKA.”

http://www.ncbi.nlm.nih.gov/pubmed/27624384

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Cannabinoid WIN-55,212-2 mesylate inhibits interleukin-1β induced matrix metalloproteinase and tissue inhibitor of matrix metalloproteinase expression in human chondrocytes

Osteoarthritis and Cartilage Home

“Interleukin-1β (IL-1β) is involved in the up-regulation of matrix metalloproteinases (MMPs) leading to cartilage degradation.

Cannabinoids are anti-inflammatory and reduce joint damage in animal models of arthritis.

This study aimed to determine a mechanism whereby the synthetic cannabinoid WIN-55,212-2 mesylate (WIN-55) may inhibit cartilage degradation.

Cannabinoid WIN-55 can reduce both basal and IL-1β stimulated gene and protein expression of MMP-3 and -13. However WIN-55 also decreased basal levels of TIMP-1 and -2 mRNA.

These actions of WIN-55 suggest a mechanism by which cannabinoids may act to prevent cartilage breakdown in arthritis.”

http://www.oarsijournal.com/article/S1063-4584(13)00999-0/abstract

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Expression of Cannabinoid Receptors in Human Osteoarthritic Cartilage: Implications for Future Therapies

“Cannabinoids have shown to reduce joint damage in animal models of arthritis and reduce matrix metalloproteinase expression in primary human osteoarthritic (OA) chondrocytes.

Chondrocytes from OA joints were shown to express a wide range of cannabinoid receptors even in degenerate tissues, demonstrating that these cells could respond to cannabinoids.

Cannabinoids designed to bind to receptors inhibiting the catabolic and pain pathways within the arthritic joint, while avoiding psychoactive effects, could provide potential arthritis therapies.

Cannabinoids were originally derived from the cannabis plant, Cannabis sativa, which has been used medicinally and recreationally for many years because of its anti-inflammatory, analgesic, and psychoactive properties.”

http://online.liebertpub.com/doi/full/10.1089/can.2015.0001

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