Tag Archives: cannabinoid receptors

Inhibitory effect of cannabichromene, a major non-psychotropic cannabinoid extracted from Cannabis sativa, on inflammation-induced hypermotility in mice.

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“BACKGROUND AND PURPOSE:

Cannabichromene (CBC) is a major non-psychotropic phytocannabinoid that inhibits endocannabinoid inactivation and activates the transient receptor potential ankyrin-1 (TRPA1). Both endocannabinoids and TRPA1 may modulate gastrointestinal motility. Here, we investigated the effect of CBC on mouse intestinal motility in physiological and pathological states.”

“CONCLUSION AND IMPLICATIONS:

CBC selectively reduces inflammation-induced hypermotility in vivo in a manner that is not dependent on cannabinoid receptors or TRPA1.”

http://www.ncbi.nlm.nih.gov/pubmed/22300105

Cannabinoid receptor type 2 activation induces a microglial anti-inflammatory phenotype and reduces migration via MKP induction and ERK dephosphorylation

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“Cannabinoid receptor type 2 (CBR2) inhibits microglial reactivity through a molecular mechanism yet to be elucidated. We hypothesized that CBR2 activation induces an anti-inflammatory phenotype in microglia by inhibiting extracellular signal-regulated kinase (ERK) pathway, via mitogen-activated protein kinase-phosphatase (MKP) induction. MKPs regulate mitogen activated protein kinases, but their role in the modulation of microglial phenotype is not fully understood.”

“Our results uncover a cellular microglial pathway triggered by CBR2 activation. These data suggest that the reduction of pro-inflammatory factors and microglial migration via MKP-3 induction is part of the mechanism of action of CBR2 agonists. These findings may have clinical implications for further drug development.”

“In summary, our current results uncovered a cellular mechanism of action of CBR2 agonists that produces a microglial anti-inflammatory phenotype, which may modulate microglial motility in vivo. We identified MKP-3 and microglial migration as potential new targets for drug development. The clinical utility of CBR2 agonists is supported by their analgesic efficacy and their lack of neurological side effects in animal models of postoperative or neuropathic pain.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2704199/

A peripheral cannabinoid mechanism suppresses spinal fos protein expression and pain behavior in a rat model of inflammation.

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  “The present studies were conducted to test the hypothesis that systemically inactive doses of cannabinoids suppress inflammation-evoked neuronal activity in vivo via a peripheral mechanism…

…These data provide direct evidence that a peripheral cannabinoid mechanism suppresses the development of inflammation-evoked neuronal activity at the level of the spinal dorsal horn and implicate a role for CB(2) and CB(1) in peripheral cannabinoid modulation of inflammatory nociception.”

http://www.ncbi.nlm.nih.gov/pubmed/12617970

Selective activation of cannabinoid CB(2) receptors suppresses spinal fos protein expression and pain behavior in a rat model of inflammation.

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“Activation of cannabinoid CB(2) receptors attenuates thermal nociception in untreated animals while failing to produce centrally mediated effects such as hypothermia and catalepsy. The present study was conducted to test the hypothesis that activation of CB(2) in the periphery suppresses the development of inflammatory pain as well as inflammation-evoked neuronal activity at the level of the CNS…”

“These data provide evidence that actions at cannabinoid CB(2) receptors are sufficient to suppress inflammation-evoked neuronal activity at rostral levels of processing in the spinal dorsal horn…”

http://www.ncbi.nlm.nih.gov/pubmed/12809695

Activation of peripheral cannabinoid CB1 and CB2 receptors suppresses the maintenance of inflammatory nociception: a comparative analysis

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“Effects of locally administered agonists and antagonists for cannabinoid CB1 and CB2 receptors on mechanical and thermal hypersensitivity were compared after the establishment of chronic inflammation.”

“Cannabinoids act locally through distinct CB1 and CB2 mechanisms to suppress mechanical hypersensitivity after the establishment of chronic inflammation, at doses that produced modest changes in thermal hyperalgesia. Additive antihyperalgesic effects were observed following prophylactic co-administration of the CB1– and CB2-selective agonists. Our results suggest that peripheral cannabinoid antihyperalgesic actions may be exploited for treatment of inflammatory pain states.”

“In summary, our results demonstrate that selective activation of CB1 or CB2 receptors in the inflamed paw is sufficient to suppress tactile allodynia and mechanical hyperalgesia. This suppression is observed under conditions in which only a partial suppression of thermal hyperalgesia was observed. Collectively, our data suggest that peripheral cannabinoid analgesic mechanisms may be exploited to suppress the tactile hypersensitivity observed in chronic inflammatory pain states.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2042894/

Cannabidiol, extracted from Cannabis sativa, selectively inhibits inflammatory hypermotility in mice

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 “Cannabidiol is a Cannabis-derived non-psychotropic compound that exerts a plethora of pharmacological actions, including anti-inflammatory, neuroprotective and antitumour effects, with potential therapeutic interest. However, the actions of cannabidiol in the digestive tract are largely unexplored. In the present study, we investigated the effect of cannabidiol on intestinal motility in normal (control) mice and in mice with intestinal inflammation.”

“Cannabidiol selectively reduces croton oil-induced hypermotility in mice in vivo and this effect involves cannabinoid CB1 receptors and FAAH. In view of its low toxicity in humans, cannabidiol may represent a good candidate to normalize motility in patients with inflammatory bowel disease.”

“The plant Cannabis sativa contains more than 60 terpenophenolic compounds, named phytocannabinoids. The best-studied phytocannabinoid is Δ9-tetrahydrocannabinol, which binds specific G-protein-coupled receptors, named cannabinoid (CB1 and CB2) receptors. The well-known psychotropic effects of Δ9-tetrahydrocannabinol, which are largely mediated by activation of brain cannabinoid CB1 receptors, have always raised a number of clinical and ethical problems. Therefore, a valid therapeutic alternative may be the use of non-psychotropic phytocannabinoids, including cannabidiol (CBD). CBD, unlike Δ9-tetrahydrocannabinol, has very low affinity for both cannabinoid CB1 and CB2 receptors, although it has been proposed that CBD may modulate endocannabinoid function through its ability to inhibit the hydrolysis of anandamide and to act as a transient receptor potential vanilloid 1 agonist. CBD is a major component of Sativex, a preparation of cannabinoids, which has been approved by Health Canada for the treatment of neuropathic pain in multiple sclerosis.”

“The pharmacological profile of CBD has been recently reviewed. Briefly stated, CBD has been shown to exert (1) antioxidant, neuroprotective and antiproliferative actions in cultured cells and (2) anti-anxiety, hypnotic, anticonvulsant, neuroprotective, antinausea, anti-ischaemic, anticancer and notably anti-inflammatory effects in rodents in vivo. The anti-inflammatory effects of CBD have been demonstrated in both acute and chronic experimental models of inflammation, that is, paw oedema and arthritis.”

“In conclusion, we have shown that the marijuana component CBD normalize intestinal motility in an experimental model of ileitis. In vitro results showed antispasmodic actions of CBD on intestinal ileal segments. The inhibitory effect of CBD involves, at least in vivo, cannabinoid CB1 receptors and FAAH. In view of its safety records in humans (an average daily dose of about 700 mg/day for 6 weeks was found to be non-toxic, relative to placebo, in clinical trials; and because CBD reduced motility during inflammation and not in physiological conditions, CBD might be considered as a good candidate to be clinically evaluated for the treatment of hypermotility associated with inflammatory bowel disease.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2451037/

Cannabinoids as novel anti-inflammatory drugs

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Figure 1

“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.”

“Cannabis, commonly known as marijuana, is a product of the Cannabis sativa plant and the active compounds from this plant are collectively referred to as cannabinoids. For several centuries, marijuana has been used as an alternative medicine in many cultures and, recently, its beneficial effects have been shown in: the treatment of nausea and vomiting associated with cancer chemotherapy; anorexia and cachexia seen in HIV/AIDS patients; and in neuropathic pain and spasticity in multiple sclerosis. Cannabinoid pharmacology has made important advances in recent years after the discovery of the cannabinoid receptors (CB1 and CB2). Cannabinoid receptors and their endogenous ligands have provided an excellent platform for the investigation of the therapeutic effects of cannabinoids. It is well known that CB1 and CB2 are heterotrimeric Gi/o-protein-coupled receptors and that they are both expressed in the periphery and the CNS. However, CB1 expression is predominant in the CNS, especially on presynaptic nerves, and CB2 is primarily expressed on immune cells.”

“Cannabinoids are potent anti-inflammatory agents and they exert their effects through induction of apoptosis, inhibition of cell proliferation, suppression of cytokine production and induction of T-regulatory cells (Tregs).”

“Executive summary

  • Cannabinoids, the active components of Cannabis sativa, and endogenous cannabinoids mediate their effects through activation of specific cannabinoid receptors known as cannabinoid receptor 1 and 2 (CB1 and CB2).
  • The cannabinoid system has been shown both in vivo and in vitro to be involved in regulating the immune system through its immunomodulatory properties.
  • Cannabinoids suppress inflammatory response and subsequently attenuate disease symptoms. This property of cannabinoids is mediated through multiple pathways such as induction of apoptosis in activated immune cells, suppression of cytokines and chemokines at inflammatory sites and upregulation of FoxP3+ regulatory T cells.
  • Cannabinoids have been tested in several experimental models of autoimmune disorders such as multiple sclerosis, rheumatoid arthritis, colitis and hepatitis and have been shown to protect the host from the pathogenesis through induction of multiple anti-inflammatory pathways.
  • Cannabinoids may also be beneficial in certain types of cancers that are triggered by chronic inflammation. In such instances, cannabinoids can either directly inhibit tumor growth or suppress inflammation and tumor angiogenesis.”                      http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2828614/

News about therapeutic use of cannabis and endocannabinoid system.

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“Growing basic research in recent years led to the discovery of the endocannabinoid system with a central role in neurobiology. New evidence suggests a therapeutic potential of cannabinoids in cancer chemotherapy-induced nausea and vomiting as well as in pain, spasticity and other symptoms in multiple sclerosis and movement disorders. Results of large randomized clinical trials of oral and sublingual Cannabis extracts will be known soon and there will be definitive answers to whether Cannabis has any therapeutic potential. Although the immediate future may lie in plant-based medicines, new targets for cannabinoid therapy focuses on the development of endocannabinoid degradation inhibitors which may offer site selectivity not afforded by cannabinoid receptor agonists.”  http://www.ncbi.nlm.nih.gov/pubmed/15033046

http://www.elsevier.es/es-revista-medicina-clinica-2-linkresolver-novedades-sobre-las-potencialidades-terapeuticas-13059327

Cannabidiol for neurodegenerative disorders: important new clinical applications for this phytocannabinoid?

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Abstract

“Cannabidiol (CBD) is a phytocannabinoid with therapeutic properties for numerous disorders exerted through molecular mechanisms that are yet to be completely identified. CBD acts in some experimental models as an anti-inflammatory, anticonvulsant, antioxidant, antiemetic, anxiolytic and antipsychotic agent, and is therefore a potential medicine for the treatment of neuroinflammation, epilepsy, oxidative injury, vomiting and nausea, anxiety and schizophrenia, respectively. The neuroprotective potential of CBD, based on the combination of its anti-inflammatory and antioxidant properties, is of particular interest and is presently under intense preclinical research in numerous neurodegenerative disorders. In fact, CBD combined with Δ(9) -tetrahydrocannabinol is already under clinical evaluation in patients with Huntington’s disease to determine its potential as a disease-modifying therapy. The neuroprotective properties of CBD do not appear to be exerted by the activation of key targets within the endocannabinoid system for plant-derived cannabinoids like Δ(9) -tetrahydrocannabinol, i.e. CB(1) and CB(2) receptors, as CBD has negligible activity at these cannabinoid receptors, although certain activity at the CB(2) receptor has been documented in specific pathological conditions (i.e. damage of immature brain). Within the endocannabinoid system, CBD has been shown to have an inhibitory effect on the inactivation of endocannabinoids (i.e. inhibition of FAAH enzyme), thereby enhancing the action of these endogenous molecules on cannabinoid receptors, which is also noted in certain pathological conditions. CBD acts not only through the endocannabinoid system, but also causes direct or indirect activation of metabotropic receptors for serotonin or adenosine, and can target nuclear receptors of the PPAR family and also ion channels.”

http://www.ncbi.nlm.nih.gov/pubmed/22625422