The Endocannabinoid System and Sex Steroid Hormone-Dependent Cancers.

“The “endocannabinoid system (ECS)” comprises the endocannabinoids, the enzymes that regulate their synthesis and degradation, the prototypicalcannabinoid receptors (CB1 and CB2), some noncannabinoid receptors, and an, as yet, uncharacterised transport system.

Recent evidence suggests that both cannabinoid receptors are present in sex steroid hormone-dependent cancer tissues and potentially play an important role in those malignancies.

Sex steroid hormones regulate the endocannabinoid system and the endocannabinoids prevent tumour development through putative protective mechanisms that prevent cell growth and migration, suggesting an important role for endocannabinoids in the regulation of sex hormone-dependent tumours and metastasis.

Here, the role of the endocannabinoid system in sex steroid hormone-dependent cancers is described and the potential for novel therapies assessed.”

http://www.ncbi.nlm.nih.gov/pubmed/24369462

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Involvement of cannabinoid receptors in peripheral and spinal morphine analgesia.

“The interactions between the cannabinoid and opioid systems for pain modulation are reciprocal. However, the role and the importance of the cannabinoid system in the antinociceptive effects of opioids remain uncertain. We studied these interactions with the goal of highlighting the involvement of the cannabinoid system in morphine-induced analgesia.

In both phases of the formalin test, intra paw and intrathecal morphine produced similar antinociceptive effects in C57BL/6, cannabinoid type 1 and type 2 receptor wildtype (respectively cnr1WT and cnr2WT) mice. In cnr1 and cnr2 knockout (KO) mice, at the dose used the antinociceptive effect of intra paw morphine in the inflammatory phase of the formalin test was decreased by 87% and 76%, respectively. Similarly, the antinociceptive effect of 0.1 μg spinal morphine in the inflammatory phase was abolished in cnr1KO mice and decreased by 90% in cnr2KO mice. Interestingly, the antinociceptive effect of morphine in the acute phase of the formalin test was only reduced in cnr1KO mice. Notably, systemic morphine administration produced similar analgesia in all genotypes, in both the formalin and the hot water immersion tail flick tests.

Because the pattern of expression of the mu opioid receptor (MOP), its binding properties and its G protein coupling remained unchanged across genotypes, it is unlikely that the loss of morphine analgesia in the cnr1KO and cnr2KO mice is the consequence of MOP malfunction or downregulation due to the absence of its heterodimerization with either the CB1 or the CB2 receptors, at least at the level of the spinal cord.”

http://www.ncbi.nlm.nih.gov/pubmed/24365460

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Fibromyalgia.

“Fibromyalgia is a chronic pain condition present in 2-4% of the population. Fibromyalgia consists of widespread pain with similarities to neuropathic pain in clinical findings, pathophysiology, and neuropharmacology. Pain is the predominant symptom and allodynia and hyperalgesia are common signs. Extreme fatigue, impaired cognition and nonrestorative sleep difficulties coexist in addition to other somatic symptoms.

Research including neuroimaging investigations shows abnormalities in neurotransmitters and an abnormal response to pain. Altered pain processing peripherally and centrally contribute to central sensitization and a dampened effect of the diffuse noxious inhibitory control (DNIC).

Successful management incorporates education of the patient in self-management skills, cognitive behavioral therapy (CBT), exercise, and drug therapy.

Tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors (SNRIs) (duloxetine and milnacipran), α2-δ ligands (gabapentin and pregabalin) are effective in reducing pain by≥30%. Some success has been shown with dopamine agonists (pramipexole), tramadol, other opioids and cannabinoids(nabilone).

Further evidence-based trials using complementary treatments are needed. Fibromyalgia is complex and requires a multidisciplinary approach to treatment. Patient self-management is key.”

http://www.ncbi.nlm.nih.gov/pubmed/24365316

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Endocannabinoid signalling in neuronal migration.

“The endocannabinoid (eCB) system consists of several endogenous lipids, their target CB1 and CB2 receptors and enzymes responsible for their synthesis and degradation. The most abundant eCB in the central nervous system (CNS), 2-arachidonoyl glycerol (2-AG), triggers a broad range of signalling events by acting on CB1, the most abundant G protein-coupled receptor in the CNS. The eCB system regulates many physiological processes including neurogenesis, axon guidance and synaptic plasticity. Recent studies have highlighted an additional important role for eCB signalling in neuronal migration, which is crucial to achieve the complex architecture and efficient wiring of the CNS. Indeed, eCB signalling controls migration both pre- and post-natally, regulating interneuron positioning in the developing cortex and hippocampus and the polarized motility of stem cell-derived neuroblasts. While these effects may contribute to cognitive deficits associated with cannabis consumption, they also provide potential opportunities for endogenous stem cell-based neuroregenerative strategies.”

http://www.ncbi.nlm.nih.gov/pubmed/24361301

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Cannabinoid Receptors as Target for Treatment of Osteoporosis: A Tale of Two Therapies

“This review summarises in vitro and in vivo findings relating to the influence of cannabinoid ligands on bone metabolism and argues in favour of the exploitation of cannabinoid receptors as targets for both anabolic and anti-resorptive therapy for treatment of complex multifaceted bone diseases such as osteoporosis.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3001217/

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The promise and dilemma of cannabinoid therapy: lessons from animal studies of bone disease.

“The endocannabinoid system plays an important role in numerous physiological processes and represents a potential drug target for diseases ranging from brain disorders to cancer…

In the aging skeleton, CB1 deficiency causes accelerated osteoporosis characterized mainly by a significant reduction in bone formation coupled to enhanced adipocyte accumulation in the bone marrow.

A similar acceleration of bone loss was also reported in aging CB2-deficient mice but found to be associated with enhanced bone turnover.

This perspective describes the role of cannabinoid ligands and their receptors in bone metabolism and highlights the promise and dilemma of therapeutic exploitation of the endocannabinoid system for treatment of bone disorders.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3868875/

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Spinal gene expression profiling and pathways analysis of a CB2 agonist (MDA7)-targeted prevention of paclitaxel-induced neuropathy.

“Patients receiving paclitaxel often develop peripheral neuropathies. We found that a novel selective cannabinoid CB2 receptor agonist (MDA7) prevents paclitaxel-induced mechanical allodynia in rats and mice…

The preventive effect of MDA7 on paclitaxel-induced peripheral allodynia in rats may be associated with genes involved in signal pathways in central sensitization, microglial activation, and neuroinflammation in the spinal cord.”

http://www.ncbi.nlm.nih.gov/pubmed/24361916

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Chronic administration during early adulthood does not alter the hormonally-dependent disruptive effects of delta-9-tetrahydrocannabinol (Δ9-THC) on complex behavior in female rats.

“This study examined whether chronic Δ9-THC during early adulthood would produce the same hormonally-dependent deficits in learning that are produced by chronic Δ9-THC during adolescence…

no significant effects of chronic treatment and no significant interaction between the chronic treatment and cannabinoid signaling. Thus, acute Δ9-THC produced hormonally-dependent effects on learning and performance behavior, but a period of chronic administration during early adulthood did not alter these effects significantly, which is contrary to what we and others have shown for chronic administration during adolescence.”

http://www.ncbi.nlm.nih.gov/pubmed/24361784

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The cytokine and endocannabinoid systems are co-regulated by NF-κB p65/RelA in cell culture and transgenic mouse models of Huntington’s disease and in striatal tissue from Huntington’s disease patients.

“Transcriptional dysregulation is a major pathological feature of Huntington’s disease (HD). The goal of this study was to understand how p65/RelA co-regulated genes, specifically those of the cytokine and endocannabinoid systems, were affected in HD. p65/RelA levels were lower in human HD tissue and R6/2 HD mice, as were the levels of the type 1 cannabinoid receptor (CB1), IL-1β, IL-8, CCL5, GM-CSF, MIP-1β, and TNFα, all of which may be regulated by p65/RelA. Activation of p65/RelA restored CB1 and CCL5 expression in STHdh cell models of HD. Therefore, p65/RelA activation may normalize the expression of some genes in HD.”

http://www.ncbi.nlm.nih.gov/pubmed/24360910

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The agonist binding mechanism of human CB2 receptor studied by molecular dynamics simulation, free energy calculation and 3D-QSAR studies.

“CB2-selective agonists have drawn attention in drug discovery, since CB2 becomes a promising target for the treatment of neuropathic pain without psychoactive or other CNS-related side effects…

A combinational exploration of both CoMFA steric and potential contour maps for CB2 affinities and the MD studied interaction modes sheds light on the structural requirements for CB2 agonists and serves as a basis for the design of novel CB2 agonists.”

http://www.ncbi.nlm.nih.gov/pubmed/24358778

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