Development and Pharmacological Characterization of Selective Blockers of 2-Arachidonoyl Glycerol Degradation with Efficacy in Rodent Models of Multiple Sclerosis and Pain.

Posted on February 19, 2016 by David

“We report the discovery of compound 4a, a potent β-lactam-based monoacylglycerol lipase (MGL) inhibitor characterized by an irreversible and stereoselective mechanism of action, high membrane permeability, high brain penetration evaluated using a human in vitro blood brain barrier model, high selectivity in binding and affinity-based proteomic profiling assays, and low in vitro toxicity.

Mode-of-action studies demonstrate that 4a, by blocking MGL, increases 2-arachidonoylglycerol, and behaves as cannabinoid (CB1/CB2) receptor indirect agonist.

Administration of 4a in mice suffering from experimental autoimmune encephalitis ameliorates the severity of the clinical symptoms in a CB1/CB2-dependent manner. Moreover, 4a produced analgesic effects in a rodent model of acute inflammatory pain, which was antagonized by CB1 and CB2 receptor antagonists/inverse agonists. 4a also relieves the neuropathic hypersensitivity induced by oxaliplatin.

Given these evidences, 4a, as MGL selective inhibitor, could represent a valuable lead for the future development of therapeutic options for multiple sclerosis and chronic pain.”

http://www.ncbi.nlm.nih.gov/pubmed/26888301

β-caryophyllene, a dietary cannabinoid, complexed with β-cyclodextrin produced anti-hyperalgesic effect involving the inhibition of Fos expression in superficial dorsal horn.

Posted on February 19, 2016 by David

“Evaluate the anti-hyperalgesic effect of the complex containing β-caryophyllene (βCP) and β-cyclodextrin (βCD) in a non-inflammatory chronic muscle pain mice model and investigated its action on superficial dorsal horn of the lumbar spinal cord.

The characterization tests indicated that βCP were efficiently incorporated into βCD. The oral treatment with βCP-βCD, at all doses tested, produced a significant reduction on mechanical hyperalgesia and a significant increase in muscle withdrawal thresholds, without produce any alteration in force. In addition, βCP-βCD was able to significantly decrease Fos expression in the superficial dorsal horn.

SIGNIFICANCE:

Thus, βCP-βCD attenuates the non-inflammatory chronic muscle pain in mice and inhibits the Fos expression in the lumbar spinal cord.”

http://www.ncbi.nlm.nih.gov/pubmed/26883973

“β-caryophyllene (BCP) is a common constitute of the essential oils of numerous spice, food plants and major component in Cannabis.” http://www.ncbi.nlm.nih.gov/pubmed/23138934

“β (beta)-cyclodextrin: 7-membered sugar ring molecule” https://en.wikipedia.org/wiki/Cyclodextrin

Medical cannabis: considerations for the anesthesiologist and pain physician.

Posted on February 8, 2016 by David

“New regulations are in place at the federal and provincial levels in Canada regarding the way medical cannabis is to be controlled. We present them together with guidance for the safe use of medical cannabis and recent clinical trials on cannabis and pain.

Health Canada has approved a new regulation on medical marijuana/cannabis, the Marihuana for Medical Purposes Regulations: The production of medical cannabis by individuals is illegal. Health Canada, however, has licensed authorized producers across the country, limiting the production to specific licenses of certain cannabis products. There are currently 26 authorized licensed producers from seven Canadian provinces offering more than 200 strains of marijuana.

We provide guidance for the safe use of medical cannabis.

The recent literature indicates that currently available cannabinoids are modestly effective analgesics that provide a safe, reasonable therapeutic option for managing chronic non-cancer-related pain.

The science of medical cannabis and the need for education of healthcare professionals and patients require continued effort. Although cannabinoids work to decrease pain, there is still a need to confirm these beneficial effects clinically and to exploit them with acceptable benefit-to-risk ratios.”

http://www.ncbi.nlm.nih.gov/pubmed/26850063

[Efficacy, tolerability and safety of cannabinoids for chronic neuropathic pain : A systematic review of randomized controlled studies].

Posted on February 3, 2016 by David

“Recently published systematic reviews came to different conclusions with respect to the efficacy, tolerability and safety of cannabinoids for treatment of chronic neuropathic pain.

Cannabinoids were marginally superior to placebo in terms of efficacy and inferior in terms of tolerability.

Cannabinoids and placebo did not differ in terms of safety during the study period.

Short-term and intermediate-term therapy with cannabinoids can be considered in selected patients with chronic neuropathic pain after failure of first-line and second-line therapies.”

http://www.ncbi.nlm.nih.gov/pubmed/26830780

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

Up-regulation of immunomodulatory effects of mouse bone-marrow derived mesenchymal stem cells by tetrahydrocannabinol pre-treatment involving cannabinoid receptor CB2.

Posted on January 30, 2016 by David

“Chronic pain is commonly and closely correlated with inflammation.

Both cannabinoid signaling and mesenchymal stem cells (MSCs) have been demonstrated to reduce inflammatory pain.

Although cannabinoid signaling is essential for mesenchymal stem cell survival and differentiation, little is known about its role in modulatory effect of MSCs on inflammation and pain sensitivity. Here we showed that mouse bone-marrow derived MSCs (BM-MSCs) expressed both cannabinoid receptor type 1 and 2 (CB1 and CB2). CB2 expression level in BM-MSCs increased with their maturation.

In addition, we found that tetrahydrocannabinol (THC) activated CB2 receptor and ERK signaling, consequently enhancing the modulation of MSCs on inflammation-associated cytokine release from lipopolysaccharides-stimulated microglia.

Consistent with in vitro data, THC pretreatment enhanced the immunomodulatory effects of BM-MSC on thermal hyperalgesia and mechanical allodynia in chronic constriction injury model, by decreasing the release of pro-inflammation cytokines.

Our study revealed the crucial role of THC in promoting the immunomodulatory effects of MSCs and proposed a new strategy to alleviate pain based on stem cells therapy.”

http://www.ncbi.nlm.nih.gov/pubmed/26824325

Dronabinol increases pain threshold in patients with functional chest pain: a pilot double-blind placebo-controlled trial.

Posted on January 30, 2016 by David

“Noncardiac chest pain is associated with poor quality of life and high care expenditure. The majority of noncardiac chest pain is either gastresophageal reflux disease related or due to esophageal motility disorders, and the rest are considered functional chest pain (FCP) due to central and peripheral hypersensitivity. Current treatment of FCP improves 40-50% of patients.

Cannabinoid receptors 1 (CB₁ ) and 2 (CB₂ ) modulate release of neurotransmitters; CB₁ is located in the esophageal epithelium and reduces excitatory enteric transmission and potentially could reduce esophageal hypersensitivity.

We performed a prospective study to evaluate its effects on pain threshold, frequency, and intensity in FCP.

Dronabinol increased pain thresholds significantly (3.0 vs. 1.0; P = 0.03) and reduced pain intensity and odynophagia compared to placebo (0.18 vs. 0.01 and 0.12 vs. 0.01, respectively, P = 0.04).

Depression and anxiety scores did not differ between the groups at baseline or after treatment.

No significant adverse effects were observed.

In this novel study, dronabinol increased pain threshold and reduced frequency and intensity of pain in FCP. Further, large scale studies are needed to substantiate these findings.”

http://www.ncbi.nlm.nih.gov/pubmed/26822791

The selective monoacylglycerol lipase inhibitor MJN110 produces opioid sparing effects in a mouse neuropathic pain model.

Posted on January 23, 2016 by David

“Serious clinical liabilities associated with the prescription of opiates for pain control include constipation, respiratory depression, pruritus, tolerance, abuse, and addiction.

A recognized strategy to circumvent these side effects is to combine opioids with other antinociceptive agents.

The combination of opiates with the primary active constituent of cannabis, Δ9-tetrahydrocannabinol, produces enhanced antinociceptive actions, suggesting that cannabinoid receptor agonists can be opioid sparing…

Here, we tested whether elevating the endogenous cannabinoid 2-arachidonylglycerol (2-AG) through the inhibition of its primary hydrolytic enzyme monoacylglycerol lipase (MAGL), will produce opioid sparing effects…

These findings, taken together, suggest that MAGL inhibition produces opiate sparing events with diminished tolerance, constipation, and cannabimemetic side effects.”

http://www.ncbi.nlm.nih.gov/pubmed/26791602

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

Evaluating Sativex® in Neuropathic Pain Management: A Clinical and Neurophysiological Assessment in Multiple Sclerosis.

Posted on January 15, 2016 by David

“Pain is a common symptom of MS, affecting up to 70% of patients.

Pain treatment is often unsatisfactory, although emerging drugs (including cannabinoids) are giving encouraging results.

The aim of our study was to better investigate the role of Sativex® in improving pain in multiple sclerosis (MS) patients by means of either clinical or neurophysiological assessment.

One month of drug administration in MS patients with neuropathic pain successfully reduced pain rating and improved quality of life.

Our data suggest that Sativex may be effective in improving MS-related neuropathic pain, maybe through its action on specific cortical pathways.”

http://www.ncbi.nlm.nih.gov/pubmed/26764336

The Role of the Brain’s Endocannabinoid System in Pain and Its Modulation by Stress.

Posted on December 8, 2015 by David

“Stress has a complex, bidirectional modulatory influence on pain. Stress may either reduce (stress-induced analgesia) or exacerbate (stress-induced hyperalgesia) pain depending on the nature, duration, and intensity of the stressor.

The endogenous cannabinoid (endocannabinoid) system is present throughout the neuroanatomical pathways that mediate and modulate responses to painful stimuli.

The specific role of the endocannabinoid system in the brain in pain and the modulation of pain by stress is reviewed herein.

We first provide a brief overview of the endocannabinoid system, followed by a review of the evidence that the brain’s endocannabinoid system modulates pain.

We provide a comprehensive evaluation of the role of the endocannabinoid system supraspinally, and particularly in the rostral ventromedial medulla, periaqueductal gray, amygdala, and prefrontal cortex, in pain, stress-induced analgesia, and stress-induced hyperalgesia.

Increased understanding of endocannabinoid-mediated regulation of pain and its modulation by stress will inform the development of novel therapeutic approaches for pain and its comorbidity with stress-related disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/26638768

Self-Medication of Somatic and Psychiatric Conditions Using Botanical Marijuana.

Posted on November 28, 2015 by David

“As a complement to research evaluating botanical marijuana as a medical therapy for various somatic and psychiatric conditions, there is a growing body of research assessing marijuana users’ self-reports of the symptoms and conditions for which they use marijuana without a physician’s recommendation.

As part of two larger web-based surveys and one in-situ survey at an outdoor marijuana festival, we asked regular marijuana users if they consumed the drug without a physician’s recommendation and, if so, to describe (or select from a checklist) the conditions for which they used marijuana as a medication.

Participants reported using marijuana to self-medicate a wide variety of both somatic conditions (such as pain, diabetes, and irritable bowel syndrome) and psychiatric conditions (such as depression, anxiety, and insomnia).

Because fewer than half of the American states, and only a few countries, allow physicians to recommend medicinal marijuana, these findings may be of interest to clinicians as they treat patients, to lawmakers and policymakers as they consider legislation allowing physicians to recommend botanical marijuana for somatic and psychiatric conditions, and to researchers evaluating conditions that individuals elect to self-medicate using botanical marijuana.”

http://www.ncbi.nlm.nih.gov/pubmed/26595140