CB1R was involved in the nerve growth of ectopic cyst associated with endometriosis.”
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“Cannabis was extensively used as a medicine throughout the developed world in the nineteenth century but went into decline early in the twentieth century ahead of its emergence as the most widely used illicit recreational drug later that century. Recent advances in cannabinoid pharmacology alongside the discovery of the endocannabinoid system (ECS) have re-ignited interest in cannabis-based medicines.
The ECS has emerged as an important physiological system and plausible target for new medicines. Its receptors and endogenous ligands play a vital modulatory role in diverse functions including immune response, food intake, cognition, emotion, perception, behavioural reinforcement, motor co-ordination, body temperature, wake/sleep cycle, bone formation and resorption, and various aspects of hormonal control. In disease it may act as part of the physiological response or as a component of the underlying pathology.
In the forefront of clinical research are the cannabinoids delta-9-tetrahydrocannabinol and cannabidiol, and their contrasting pharmacology will be briefly outlined. The therapeutic potential and possible risks of drugs that inhibit the ECS will also be considered. This paper will then go on to review clinical research exploring the potential of cannabinoid medicines in the following indications: symptomatic relief in multiple sclerosis, chronic neuropathic pain, intractable nausea and vomiting, loss of appetite and weight in the context of cancer or AIDS, psychosis, epilepsy, addiction, and metabolic disorders.”
http://www.ncbi.nlm.nih.gov/pubmed/24006213
http://onlinelibrary.wiley.com/doi/10.1002/dta.1529/abstract
“The term ‘endocannabinoid’ – originally coined in the mid-1990s after the discovery of membrane receptors for the psychoactive principle in Cannabis, Delta9-tetrahydrocannabinol and their endogenous ligands – now indicates a whole signalling system that comprises cannabinoid receptors, endogenous ligands and enzymes for ligand biosynthesis and inactivation. This system seems to be involved in an ever-increasing number of pathological conditions. With novel products already being aimed at the pharmaceutical market little more than a decade since the discovery of cannabinoid receptors, the endocannabinoid system seems to hold even more promise for the future development of therapeutic drugs. We explore the conditions under which the potential of targeting the endocannabinoid system might be realized in the years to come.” http://www.ncbi.nlm.nih.gov/pubmed/15340387
“Cannabis sativa is one of the oldest herbal remedies known to man. Over the past four thousand years, it has been used for the treatment of numerous diseases but due to its psychoactive properties, its current medicinal usage is highly restricted. In this review, we seek to highlight advances made over the last forty years in the understanding of the mechanisms responsible for the effects of cannabis on the human body and how these can potentially be utilized in clinical practice. During this time, the primary active ingredients in cannabis have been isolated, specific cannabinoid receptors have been discovered and at least five endogenous cannabinoid neurotransmitters (endocannabinoids) have been identified. Together, these form the framework of a complex endocannabinoid signalling system that has widespread distribution in the body and plays a role in regulating numerous physiological processes within the body. Cannabinoid ligands are therefore thought to display considerable therapeutic potential and the drive to develop compounds that can be targeted to specific neuronal systems at low enough doses so as to eliminate cognitive side effects remains the ‘holy grail’ of endocannabinoid research.”
“Human tissues express cannabinoid CB(1) and CB(2) receptors that can be activated by endogenously released ‘endocannabinoids’ or exogenously administered compounds in a manner that reduces the symptoms or opposes the underlying causes of several disorders in need of effective therapy. Three medicines that activate cannabinoid CB(1)/CB(2) receptors are now in the clinic: Cesamet (nabilone), Marinol (dronabinol; Δ(9)-tetrahydrocannabinol (Δ(9)-THC)) and Sativex (Δ(9)-THC with cannabidiol). These can be prescribed for the amelioration of chemotherapy-induced nausea and vomiting (Cesamet and Marinol), stimulation of appetite (Marinol) and symptomatic relief of cancer pain and/or management of neuropathic pain and spasticity in adults with multiple sclerosis (Sativex). This review mentions several possible additional therapeutic targets for cannabinoid receptor agonists. These include other kinds of pain, epilepsy, anxiety, depression, Parkinson’s and Huntington’s diseases, amyotrophic lateral sclerosis, stroke, cancer, drug dependence, glaucoma, autoimmune uveitis, osteoporosis, sepsis, and hepatic, renal, intestinal and cardiovascular disorders. It also describes potential strategies for improving the efficacy and/or benefit-to-risk ratio of these agonists in the clinic. These are strategies that involve (i) targeting cannabinoid receptors located outside the blood-brain barrier, (ii) targeting cannabinoid receptors expressed by a particular tissue, (iii) targeting upregulated cannabinoid receptors, (iv) selectively targeting cannabinoid CB(2) receptors, and/or (v) adjunctive ‘multi-targeting’.” https://www.ncbi.nlm.nih.gov/pubmed/23108552
“Dr. Phillip Leveque has spent his life as a Combat Infantryman, Physician, Toxicologist and Pharmacologist.
(MOLALLA, Ore.) – I don’t think I have to explain what this is to anybody. If you have it, you know it. Endometriosis is graded in stages I,II, III & IV, with stage I being “minimized” inconvenience while stage IV is severe and usually requires surgery.
As a physician, I had known about endometriosis for years and that some women become narcotic addicts because of it. Pre Menstrual Tension (PMS) may be concurrent though different and I had many PMS patients as well. Some of them became addicts also. I was not surprised when lady patients came to our clinics offering chart notes that they had been prescribed every conceivable analgesic and other medications but they also told me marijuana works better than any regular prescription.
I have a severe pain problem myself caused by too high of a concentration of spinal anesthesia. I got disgusted by the anesthesiologist telling me he didn’t cause it but I got a new understanding for patients in pain.
If the patient says marijuana works for pain, I believe them. Actually in Oregon about sixty percent of patients have some chronic pain syndrome of nerve, muscle, joint, bone, intestinal or genitourinary. It doesn’t seem to matter whatever the source of pain, the bottom line is that MJ gives relief.
I presume stage I endometriosis and minor PMS are effectively treated with aspirin-like drugs, but when the pain etc. is in the moderate/severe level, the ladies have found out by themselves that marijuana/cannabis is effective without the hazard of narcotic addiction or alcoholism.
The U.S. government publicizes that as many as 77 million Americans have used marijuana and perhaps ten million use it frequently.
Marijuana as folk medicine has been used in the U.S. since the middle 1800’s and probably in Mexico and Latin America since the Spanish introduced it in the late 1500’s.
It is no longer amazing to me when a patient tells me of some new disease for which they have discovered marijuana treatment is beneficial.
It is time the DEA and its hoodlums backed off and allow the therapeutic use of medical marijuana, as more and more people are reverting to this tried and true “folk medicine” everyday.”
http://www.salem-news.com/articles/january032008/endo_med_1308.php
“The endocannabinoid system consists of an array of endogenously produced bioactive lipids that activate cannabinoid 1 (CB1) and 2 (CB2) receptors. Alterations of this system have been described in almost every category of disease. These changes can be protective or maladaptive, making the endocannabinoid network an attractive therapeutic target. Little is known about the potential role of endocannabinoids in endometriosis development although this is a topic worthy of further investigation since endocannabinoid modulators have recently been shown to affect specific mechanisms critical to endometriosis establishment and maintenance. A literature review was herein performed with the aim of defining the regulation and function of the endocannabinoid signaling in in vitro and animal models of endometriosis. The components of the endocannabinoid system, CB1 and CB2 receptors and the enzymes N-acylphosphatidylethanolamine-phospholipase D and fatty acid amide hydrolase are differentially regulated throughout the menstrual cycle in the endometrium and are expressed in deep endometriotic nodules and in sensory and sympathetic neurons innervating the lesions. Selective cannabinoid receptor agonists, such as WIN 55212-2, appear to have a favorable action in limiting cell proliferation and in controlling pain symptoms. Conversely, endometrial cell migration tends to be stimulated by receptor agonists. The phosphatidylinositol 3-kinase/Akt and extracellular signal-regulated kinase 1/2 pathways seem to be involved in these processes. However, the underlying mechanisms of action are only just beginning to unfold. Given the complexity of the system, further studies are needed to clarify whether the endocannabinoid system might represent a promising target for endometriosis.”
Endometriosis is a disorder in which the endometrium forms growths outside the uterus and is associated with chronic pain. Recent evidence suggests that endometrial motility plays a role in the aetiology of endometriosis. The endocannabinoid system regulates cellular migration. Given the growing involvement of the endocannabinoids in reproduction, we investigated the role of the endocannabinoid system in migration of endometrial cells.
Migration of the human endometrial HEC-1B cells was assayed. Standard PCR techniques were used to determine the presence of the GPCR, GPR18, in HEC-1B cells, and p44/42 MAPK was assayed in stably transfected HEK293-GPR18 cells to determine receptor specificity for known cannabinoid agonists and antagonists. N-arachidonoyl ethanolamine (AEA) metabolism was measured, using HPLC/MS/MS for lipid analysis.
AEA, Δ(9) -tetrahydrocannabinol (Δ(9) -THC) and N-arachidonoyl glycine (NAGly) induce migration of HEC-1B cells through cannabinoid CB(1) receptor-independent mechanisms. MAPK activation in HEK293-GPR18 cells revealed novel pharmacology for known CB(1) and CB(2) receptor ligands at GPR18 receptors, including Δ(9) -THC, which activates MAPK at nanomolar concentrations, whereas WIN 55212-2, CP55940, JWH-133 and JWH-015, and arachidonyl-1-hydroxy-2-propylamide (R1-methanandamide) had no effect. Moreover, HEC-1B migration and MAPK activation by NAGly and Δ(9) -THC were antagonized by Pertussis toxin, AM251 and cannabidiol.
An understanding of the function and regulation of GPR18 and its molecular interactions with endogenous ligands, and how phytocannabinoids play a role with GPR18 signalling is vital if we are to comprehensively assess the function of the cannabinoid signalling system in human health and disease. LINKED ARTICLES: This article is commented on by Alexander, pp. 2411-2413 of this issue and is part of a themed section on Cannabinoids in Biology and Medicine. To view Alexander visit http://dx.doi.org/10.1111/j.1476-5381.2011.01731.x. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-8. To view Part I of Cannabinoids in Biology and Medicine visit http://dx.doi.org/10.1111/bph.2011.163.issue-7.”
“Deep infiltrating endometriosis (DIE) is characterized by chronic pain, hyperproliferation of endometriotic cells and fibrosis. Since cannabinoids are endowed with antiproliferative and antifibrotic properties, in addition to their psychogenic and analgesic effects, cannabinoid agonists have been evaluated in DIE both in vitro and in vivo. The in vitro effects of the cannabinoid agonist WIN 55212-2 were evaluated on primary endometriotic and endometrial stromal and epithelial cell lines extracted from patients with or without DIE. Cell proliferation was determined by thymidine incorporation and production of reactive oxygen species by spectrofluorometry. ERK and Akt pathways were studied by immunoblotting. Immunoblotting of α-smooth muscle actin was studied as evidence of myofibroblastic transformation. The in vivo effects of WIN 55212-2 were evaluated on Nude mice implanted with human deep infiltrating endometriotic nodules. The in vitro treatment of stromal endometriotic cells by WIN 55212-2 decreased cell proliferation, reactive oxygen species production, and α-smooth muscle actin expression. The decrease in cell proliferation induced by WIN 55212-2 was not associated with a decrease in ERK activation, but was associated with the inhibition of Akt activation. WIN 55212-2 abrogated the growth of endometriotic tissue implanted in Nude mice. Cannabinoid agonists exert anti-proliferative effects on stromal endometriotic cells linked to the inhibition of the Akt pathway. These beneficial effects of cannabinoid agonists on DIE have been confirmed in vivo.”
“The cannabinoids are well known for their psychogenic effects and their role in inflammation and immunity. They are also endowed with properties that can be used in the control of three major aspects of DIE: hyperproliferation, fibrosis, and chronic pain. Because of their implication in proliferation, apoptosis, and angiogenesis, the cannabinoids control cell growth. Their antiproliferative effects result from the inhibition of growth factors and the deregulation of such signaling pathways as Ras-Raf-MKKK1-ERK1/2, PI3K-Akt/PKB-mTOR and c-Jun N-terminal kinase-MAPK. These mechanisms have suggested new targets in cancer treatment and also in endometriosis, since endometriotic cells have a hyperproliferative phenotype and pro-angiogenic properties. In addition, several experimental studies have reported an antifibrotic role of cannabinoid agonists. If such antifibrotic effect of cannabinoid agonists could be demonstrated in DIE it would allow a less extensive surgery. Finally, cannabinoids have analgesic properties and have been used for a long time in treating chronic pain.“
“Therefore, we have evaluated the effects of cannabinoid agonists in vitro on cells extracted from biopsies of deep infiltrating endometriosis and in vivo on a mouse model of endometriosis. We conclude from our data that cannabinoid agonists represent a promising approach in the treatment of DIE.”
“In conclusion, WIN 55212-2 has in vitro antiproliferative and antifibrotic effects in deep infiltrating endometriotic cells. The antiproliferative effect is linked to the inactivation of the Akt pathway. The effectiveness of WIN 55212-2 in vitro, confirmed in vivo in a mouse model of DIE, suggests that the cannabinoid agonists represent a promising therapeutic approach in the treatment of DIE.”
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2993285/
“Together the findings suggest that the endocannabinoid system is involved in endometriosis and its associated pain via CB1 receptors and innervation of the ectopic growths. Using the rat model, we performed a combination of immunohistochemical and pharmacological studies to test this hypothesis and assess the endocannabinoid system’s potential as a target for new therapies.”
“These studies in a rat model of endometriosis provide evidence that endocannabinoids might regulate the innervation of the disease’s abnormal growths and that exogenous cannabinoid agents can be effective in reducing endometriosis symptoms. The fact that CB1 receptor expression is greater in the cysts than healthy uterus from the same rats suggests that treatments to activate CB1 receptors (either directly by CB1 agonists or indirectly by increasing relevant endocannabinoid levels) could be developed with minimal effects on uterine function. Although the rat model parallels many aspects of endometriosis in women, there are of course significant differences. However, when considered together with the past history of successful use of cannabinoids for alleviation of gynecological pains, and insofar as findings in rats can model mechanisms of endometriosis-related signs and symptoms, the present results suggest that approaches targeted at the endocannbinoid system represent a promising new direction for developing badly-needed new treatments for pain suffered by women with endometriosis.”