Tag Archives: Cannabinoids

Emerging targets in treating pain.

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“Chronic pain poses an enormous socioeconomic burden for the more than 30% of people who suffer from it, costing over $600 billion per year in the USA. In recent years, there has been a surge in preclinical and clinical research endeavors to try to stem this epidemic. Preclinical studies have identified a wide array of potential targets, with some of the most promising translational research being performed on novel opioid receptors, cannabinoid receptors, selective ion channel blockers, cytokine inhibitors, nerve growth factor inhibitors, N-methyl-D-aspartate receptor antagonists, glial cell inhibitors, and bisphosphonates.

SUMMARY:

There are many obstacles for the development of effective medications to treat chronic pain, including the inherent challenges in identifying pathophysiological mechanisms, the overlap and multiplicity of pain pathways, and off-target adverse effects stemming from the ubiquity of drug target receptor sites and the lack of highly selective receptor ligands. Despite these barriers, the number and diversity of potential therapies have continued to grow, to include disease-modifying and individualized drug treatments.”

http://www.ncbi.nlm.nih.gov/pubmed/26087270

http://www.thctotalhealthcare.com/category/pain-2/

Endocannabinoids drive the acquisition of an alternative phenotype in microglia.

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“The ability of microglia to acquire diverse states of activation, or phenotypes, reflects different features that are determinant for their contribution to homeostasis in the adult CNS, and their activity in neuroinflammation, repair or immunomodulation.

Despite the widely reported immunomodulatory effects of cannabinoids in both the peripheral immune system and the CNS, less is known about how the endocannabinoid signaling system (eCBSS) influence the microglial phenotype.

The general aim of the present study was to investigate the role of endocannabinoids in microglia polarization by using microglia cell cultures.

We show that alternative microglia (M2a) and acquired deactivated microglia (M2c) exhibit changes in the eCB machinery that favor the selective synthesis of 2-AG and AEA, respectively.

Once released, these eCBs might be able to act through CB1 and/or CB2 receptors in order to influence the acquisition of an M2 phenotype.

We present three lines of evidence that the eCBSS is critical for the acquisition of the M2 phenotype: (i) M2 polarization occurs on exposure to the two main endocannabinoids 2-AG and AEA in microglia cultures; (ii)cannabinoid receptor antagonists block M2 polarization; and, (iii) M2 polarization is dampened in microglia from CB2 receptor knockout mice.

Taken together, these results indicate the interest of eCBSS for the regulation of microglial activation in normal and pathological conditions.”

http://www.ncbi.nlm.nih.gov/pubmed/26086345

Cannabinoid CB2 Receptors in a Mouse Model of Aβ Amyloidosis: Immunohistochemical Analysis and Suitability as a PET Biomarker of Neuroinflammation.

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“In Alzheimer’s disease (AD), one of the early responses to Aβ amyloidosis is recruitment of microglia to areas of new plaque. Microglial receptors such as cannabinoid receptor 2 (CB2) might be a suitable target for development of PET radiotracers that could serve as imaging biomarkers of Aβ-induced neuroinflammation…

The presence of CB2 immunoreactivity in neurons does not likely contribute to the enhanced CB2 PET signal in amyloid-bearing mice due to a lack of significant neuronal loss in this model. However, significant loss of neurons as seen at late stages of AD might decrease the CB2 PET signal due to loss of neuronally-derived CB2.

Thus this study in mouse models of AD indicates that a CB2-specific radiotracer can be used as a biomarker of neuroinflammation in the early preclinical stages of AD, when no significant neuronal loss has yet developed.”

http://www.ncbi.nlm.nih.gov/pubmed/26086915

http://www.thctotalhealthcare.com/category/alzheimers-disease-ad/

Coadministration of indomethacin and minocycline attenuates established paclitaxel-induced neuropathic thermal hyperalgesia: Involvement of cannabinoid CB1 receptors.

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“Taxanes such as paclitaxel, which are chemotherapeutic drugs, cause dose-dependent painful neuropathy in some patients.

We investigated whether coadministration of minocycline and indomethacin produces antinociceptive effects in mice with paclitaxel-induced neuropathic thermal hyperalgesia and if the cannabinoid system is involved…

In conclusion our results indicate that coadministration of minocycline and indomethacin abrogates established paclitaxel-induced neuropathic thermal hyperalgesia in mice, and the potentiation of the antinociceptive effects of this combination involves the cannabinoid system.”

Bi-directional CB1 receptor-mediated cardiovascular effects of cannabinoids in anaesthetized rats: role of the paraventricular nucleus.

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“The activation of cannabinoid CB1 receptors decreases and increases blood pressure (BP) in anaesthetized and conscious rats, respectively. The aim of our study was to check the possible involvement of CB1 receptors in the paraventricular nucleus of the hypothalamus (PVN) in the cardiovascular effects of cannabinoids in rats.

In conclusion, the cannabinoid CP55940 administered to the PVN of urethane-anaesthetized rats can induce depressor and pressor effects. The direction of the response probably depends on the sympathetic tone. The centrally induced hypertensive response of CP55940 can, in addition, be masked by peripheral CB1 receptors.”

http://www.ncbi.nlm.nih.gov/pubmed/26084216

Role of the Endocannabinoid System in Diabetes and Diabetic Complications.

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“Increasing evidence suggests that an overactive endocannabinoid system (ECS) may contribute to the development of diabetes by promoting energy intake and storage, impairing both glucose and lipid metabolism, and by exerting pro-apoptotic effects in pancreatic β cells, and by facilitating inflammation in pancreatic islets.

Furthermore, hyperglycemia associated with diabetes has also been implicated in triggering perturbations of the ECS amplifying the above mentioned pathological processes, eventually culminating in a vicious circle.

Compelling evidence from preclinical studies indicates that the ECS also influences diabetes-induced oxidative stress, inflammation, fibrosis, and subsequent tissue injury in target organs for diabetic complications.

In this review, we provide an update on the contribution of the ECS to the pathogenesis of diabetes and diabetic microvascular (retinopathy, nephropathy, and neuropathy) and cardiovascular complications. The therapeutic potential of targeting the ECS is also discussed.”

http://www.ncbi.nlm.nih.gov/pubmed/26076890#

http://www.thctotalhealthcare.com/category/diabetes/

The use of cannabinoids as anticancer agents.

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“It is well-established that cannabinoids exert palliative effects on some cancer-associated symptoms. In addition evidences obtained during the last fifteen years support that these compounds can reduce tumour growth in animal models of cancer.

Cannabinoids have been shown to activate an ER-stress related pathway that leads to the stimulation of autophagy-mediated cancer cell death.

In addition, cannabinoids inhibit tumour angiogenesis and decrease cancer cell migration.

The mechanisms of resistance to cannabinoid anticancer action as well as the possible strategies to develop cannabinoid-based combinational therapies to fight cancer have also started to be explored.

In this review we will summarize these observations (that have already helped to set the bases for the development of the first clinical studies to investigate the potential clinical benefit of using cannabinoids in anticancer therapies) and will discuss the possible future avenues of research in this area.” http://www.ncbi.nlm.nih.gov/pubmed/26071989

“… cannabinoids have been shown to alleviate nausea and vomit induced by chemotherapy and several cannabinoid-based medicines [Marinol (THC) and Cesamet (nabilone, a synthetic analogue of THC)] are approved for this purpose. Cannabinoids also inhibit pain, and Sativex (a standardized cannabis extract) has been approved in Canada for the treatment of cancer-associated pain. Other potential palliative effects of cannabinoids in oncology include appetite stimulation and attenuation of wasting. In addition to these palliative actions of cannabinoids in cancer patients, THC and other cannabinoids exhibit antitumour effects in animal models of cancer… a large body of scientific evidences strongly support THC and other cannabinoid agonists exert anticancer actions in preclinical models of cancer… In conclusion there exist solid scientific evidences supporting that cannabinoids exhibit a remarkable anticancer activity in preclinical models of cancer. Since these agents also show an acceptable safety profile, clinical studies aimed at testing them as single agents or in combinational therapies are urgently needed.” http://www.sciencedirect.com/science/article/pii/S0278584615001190

Neurobiological Interactions Between Stress and the Endocannabinoid System.

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“Stress affects a constellation of physiological systems in the body and evokes a rapid shift in many neurobehavioral processes.

A growing body of work indicates that the endocannabinoid (eCB) system is an integral regulator of the stress response.

In the current review, we discuss the evidence to date that demonstrates stress-induced regulation of eCB signaling and the consequential role changes in eCB signaling play with respect to many of the effects of stress.

Across a wide array of stress paradigms, studies have generally shown that stress evokes bidirectional changes in the two eCB molecules, anandamide (AEA) and 2-arachidonoyl glycerol (2-AG), with stress exposure reducing AEA levels and increasing 2-AG levels.

Additionally, in almost every brain region examined, exposure to chronic stress reliably causes a down-regulation or loss of cannabinoid type 1 (CB1) receptors.

With respect to the functional role of changes in eCB signaling during stress, studies have demonstrated that the decline in AEA appears to contribute to the manifestation of the stress response, including activation of the hypothalamic-pituitary-adrenal (HPA) axis and increases in anxiety behavior, while the increased 2-AG signaling contributes to termination and adaptation of the HPA axis, as well as potentially contributing to changes in pain perception and synaptic plasticity.

More so, translational studies have shown that eCB signaling in humans regulates many of the same domains and appears to be a critical component of stress regulation, and impairments in this system may be involved in the vulnerability to stress-related psychiatric conditions, such as depression and post-traumatic stress disorder.

Collectively, these data create a compelling argument that eCB signaling is an important regulatory system in the brain that largely functions to buffer against many of the effects of stress and that dynamic changes in this system contribute to different aspects of the stress response.”

http://www.ncbi.nlm.nih.gov/pubmed/26068727

In vivo inflammation imaging using a CB2R-targeted near infrared fluorescent probe.

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“Chronic inflammation is considered as a critical cause of a host of disorders, such as cancer, rheumatoid arthritis, atherosclerosis, and neurodegenerative diseases…

Imaging tools that can specifically target inflammation are therefore important to help reveal the role of inflammation in disease progression, and allows for developing new therapeutic strategies to ultimately improve patient care.

The purpose of this study was to develop a new in vivo inflammation imaging approach by targeting the cannabinoid receptor type 2 (CB2R), an emerging inflammation biomarker, using a unique near infrared (NIR) fluorescent probe…

The combined evidence indicates that NIR760-mbc94 is a promising inflammation imaging probe. Moreover, in vivo CB2R-targeted fluorescence imaging may have potential in the study of inflammation-related diseases.”

http://www.ncbi.nlm.nih.gov/pubmed/26069858

Does cannabis affect dopaminergic signaling in the human brain? A systematic review of evidence to date.

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“While abnormalities in multiple pathways may lead to schizophrenia, an abnormality in dopamine neurotransmission is considered to be the final common abnormality.

One would thus expect cannabis use to be associated with dopamine signaling alterations.

This is the first systematic review of all studies, both observational as well as experimental, examining the acute as well as chronic effect of cannabis or its main psychoactive ingredient, THC, on the dopamine system in man…

In man, there is as yet little direct evidence to suggest that cannabis use affects acute striatal dopamine release or affects chronic dopamine receptor status in healthy human volunteers. ”

http://www.ncbi.nlm.nih.gov/pubmed/26068702