Endocannabinoid Regulation of Neuroendocrine Systems.

“The hypothalamus is a part of the brain that is critical for sustaining life through its homeostatic control and integrative regulation of the autonomic nervous system and neuroendocrine systems. Neuroendocrine function in mammals is mediated mainly through the control of pituitary hormone secretion by diverse neuroendocrine cell groups in the hypothalamus.

Cannabinoid receptors are expressed throughout the hypothalamus, and endocannabinoids have been found to exert pronounced regulatory effects on neuroendocrine function via modulation of the outputs of several neuroendocrine systems.

Here, we review the physiological regulation of neuroendocrine function by endocannabinoids, focusing on the role of endocannabinoids in the neuroendocrine regulation of the stress response, food intake, fluid homeostasis, and reproductive function.

Cannabis sativa (marijuana) has a long history of recreational and/or medicinal use dating back to ancient times. It was used as an analgesic, anesthetic, and antianxiety herb as early as 2600 B.C.

The hedonic, anxiolytic, and mood-elevating properties of cannabis have also been cited in ancient records from different cultures. However, it was not until 1964 that the psychoactive constituent of cannabis, Δ(9)-tetrahydrocannabinol, was isolated and its chemical structure determined (Gaoni & Mechoulam, 1964).”

Cannabinoids in the management of chronic pain: a front line clinical perspective.

“Chronic pain is an escalating public health problem. Currently available treatments are inadequate to control chronic pain conditions, and there is a critical need for novel treatments.

Over a half century of elegant preclinical research has identified the presence of a sophisticated endocannabinoid system that is part of our natural pain and immune defense network.

Convergent work has supported the significant potential to exploit this system to decrease pain and inflammation.

Although the clinical research remains in its infancy, recent systematic reviews have found that 25 of 30 randomized controlled trials have demonstrated a significant analgesic effect.

The authors concluded that cannabinoids currently available for clinical use demonstrate a modest analgesic effect and are safe for the management of chronic pain.

There is a critical need for more translational research so that the excellent work of Dr. Itai Bab and our basic science colleagues around the world can move forward in providing novel cannabinoid-based medicines.

This should include more potent analgesics that are limited in side effects with several routes of delivery. Our patients deserve additional agents for pain control with a novel mechanism of action, and cannabinoids are the new frontier.”

http://www.ncbi.nlm.nih.gov/pubmed/26581068

The effects of endocannabinoid receptor agonist anandamide and antagonist rimonabant on opioid analgesia and tolerance in rats.

“The role of the cannabinoid (CB) system in the tolerance to analgesic effect of opioid remains obscure. The aim of the present study was to evaluate the effects of the endocannabinoid nonselective receptor agonist anandamide (AEA) and CB1 receptor antagonist rimonabant (SR141716) on morphine analgesia and tolerance in rats.

The findings suggested that AEA in combination with morphine produced a significant increase in expression of analgesic tolerance to morphine.

Conversely, cannabinoid receptor antagonist SR141716 attenuated morphine analgesic tolerance.

In addition, administration of AEA with morphine increased morphine analgesia.

In conclusion, we observed that the cannabinoid receptor agonist anandamide and CB1 receptor antagonist SR141716 plays a significant role in the opioid analgesia and tolerance.”

http://www.ncbi.nlm.nih.gov/pubmed/26374993

Microinjection of orexin-A into the rat locus coeruleus nucleus induces analgesia via cannabinoid type-1 receptors.

“Locus coeruleus (LC) nucleus is involved in noradrenergic descending pain modulation.

LC receives dense orexinergic projections from the lateral hypothalamus. Orexin-A and -B are hypothalamic peptides which modulate a variety of brain functions via orexin type-1 (OX1) and orexin type-2 (OX2) receptors.

Previous studies have shown that activation of OX1 receptors induces endocannabinoid synthesis and alters synaptic neurotransmission by retrograde signaling via affecting cannabinoid type-1 (CB1) receptors.

In the present study the interaction of orexin-A and endocannabinoids was examined at the LC level in a rat model of inflammatory pain…

This data show that, activation of OX1 receptors in the LC can induce analgesia and also the blockade of OX1 or CB1 receptors is associated with hyperalgesia during formalin test.

Our findings also suggest that CB1 receptors may modulate the analgesic effect of orexin-A.

These results outline a new mechanism by which orexin-A modulates the nociceptive processing in the LC nucleus.”

http://www.ncbi.nlm.nih.gov/pubmed/26254729

Cross-tolerance to cannabinoids in morphine-tolerant rhesus monkeys.

“Opioids remain the drugs of choice for treating moderate to severe pain, although adverse effects limit their use. Therapeutic utility might be improved by combining opioids with other drugs to enhance analgesic effects, but only if adverse effects are not similarly changed.

Cannabinoids have been shown to enhance the antinociceptive potency of opioids without increasing other effects; this study examined whether the effectiveness of cannabinoids is altered in morphine-dependent monkeys.

Tolerance developed to the antinociceptive effects of morphine and cross-tolerance developed to cannabinoids under conditions that produced modest physical dependence.

Compared with the doses examined in this study, much smaller doses of opioids have antinociceptive effects when given with cannabinoids; it is possible that tolerance will not develop to chronic treatment with opioid/cannabinoid mixtures.”

http://www.ncbi.nlm.nih.gov/pubmed/26202613

Signaling Mechanism of Cannabinoid Receptor-2 Activation-Induced β-Endorphin Release.

“Activation of cannabinoid receptor-2 (CB2) results in β-endorphin release from keratinocytes, which then acts on primary afferent neurons to inhibit nociception.

Our data also suggest that stimulation of MAPK contributes to the peripheral analgesic effect of CB2 receptor agonists.”

http://www.ncbi.nlm.nih.gov/pubmed/26108183

Emerging targets in treating pain.

“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/

Lipid nanoparticles as an emerging platform for cannabinoid delivery: physicochemical optimization and biocompatibility.

“This work aims at developing and optimizing a valuable oral delivery carrier for the cannabinoid derivative CB13, which presents a high therapeutic potential in chronic pain states that respond poorly to conventional analgesics, but also shows highly unfavorable physicochemical properties.

CB13-loaded lipid nanoparticles (LNP) formulations were developed…

The LNP formulation proposed proved to be a promising carrier for the oral delivery of CB13, a cannabinoid with high therapeutic potential in chronic pain states that currently lack a valid oral treatment.”

http://www.ncbi.nlm.nih.gov/pubmed/25996463

Cannabis has been shown to kill cancer cells

 

“The use of Cannabis for medicinal purposes dates back to ancient times.” http://www.cancer.gov/cancertopics/pdq/cam/cannabis/patient/page1

“Cannabis has been used for medicinal purposes for thousands of years.” http://www.cancer.gov/cancertopics/pdq/cam/cannabis/healthprofessional/page1

“The use of Cannabis for medicinal purposes dates back at least 3,000 years. It came into use in Western medicine in the 19th century and was said to relieve pain, inflammation, spasms, and convulsions.” http://www.cancer.gov/cancertopics/pdq/cam/cannabis/patient/page2

“Cannabis has been shown to kill cancer cells in the laboratory”  http://www.cancer.gov/cancertopics/pdq/cam/cannabis/patient/page1

“…cannabinoids may be able to kill cancer cells while protecting normal cells…

A laboratory study of delta-9-THC… showed that it damaged or killed the cancer cells…

A laboratory study of cannabidiol… showed that it caused cancer cell death…” http://www.cancer.gov/cancertopics/pdq/cam/cannabis/patient/page2

“Cannabinoids appear to kill tumor cells but do not effect their nontransformed counterparts and may even protect them from cell death.” http://www.cancer.gov/cancertopics/pdq/cam/cannabis/healthprofessional/page4

“Because cannabinoid receptors, unlike opioid receptors, are not located in the brainstem areas controlling respiration, lethal overdoses from Cannabis and cannabinoids do not occur.” http://www.cancer.gov/cancertopics/pdq/cam/cannabis/healthprofessional/page6

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

Intrathecal Injection of JWH-015 Attenuates Bone Cancer Pain Via Time-Dependent Modification of Pro-inflammatory Cytokines Expression and Astrocytes Activity in Spinal Cord.

“Cannabinoid receptor type 2 (CB2) agonists display potential analgesic effects in acute and neuropathic pain.

Overall, our results provided evidences for the persistent participation of inflammation reaction in the progression of bone cancer pain, and demonstrated that JWH-015 reduced the expression of IL-1β, IL-6, IL-18, and TNF-α and inhibited astrocytes activation in a time-dependent manner, thereby displaying an analgesic effect.”