Current evidence of cannabinoid-based analgesia obtained in preclinical and human experimental settings.

European Journal of Pain

“Cannabinoids have a long record of recreational and medical use and become increasingly approved for pain therapy. This development is based on preclinical and human experimental research summarized in this review.

Cannabinoid CB1 receptors are widely expressed throughout the nociceptive system. Their activation by endogenous or exogenous cannabinoids modulates the release of neurotransmitters. This is reflected in antinociceptive effects of cannabinoids in preclinical models of inflammatory, cancer and neuropathic pain, and by nociceptive hypersensitivity of cannabinoid receptor-deficient mice.

Cannabis-based medications available for humans mainly comprise Δ9 -tetrahydrocannabinol (THC), cannabidiol (CBD) and nabilone.

During the last 10 years, six controlled studies assessing analgesic effects of cannabinoid-based drugs in human experimental settings were reported. An effect on nociceptive processing could be translated to the human setting in functional magnetic resonance imaging studies that pointed at a reduced connectivity within the pain matrix of the brain. However, cannabinoid-based drugs heterogeneously influenced the perception of experimentally induced pain including a reduction in only the affective but not the sensory perception of pain, only moderate analgesic effects, or occasional hyperalgesic effects. This extends to the clinical setting.

While controlled studies showed a lack of robust analgesic effects, cannabis was nearly always associated with analgesia in open-label or retrospective reports, possibly indicating an effect on well-being or mood, rather than on sensory pain. Thus, while preclinical evidence supports cannabinoid-based analgesics, human evidence presently provides only reluctant support for a broad clinical use of cannabinoid-based medications in pain therapy.

SIGNIFICANCE:

Cannabinoids consistently produced antinociceptive effects in preclinical models, whereas they heterogeneously influenced the perception of experimentally induced pain in humans and did not provide robust clinical analgesia, which jeopardizes the translation of preclinical research on cannabinoid-mediated antinociception into the human setting.”

https://www.ncbi.nlm.nih.gov/pubmed/29160600

http://onlinelibrary.wiley.com/doi/10.1002/ejp.1148/abstract?systemMessage=Wiley+Online+Library+usage+report+download+page+will+be+unavailable+on+Friday+24th+November+2017+at+21%3A00+EST+%2F+02.00+GMT+%2F+10%3A00+SGT+%28Saturday+25th+Nov+for+SGT+

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Modulating the endocannabinoid pathway as treatment for peripheral neuropathic pain: a selected review of preclinical studies.

“Chemotherapy-induced neuropathic pain is a distressing and commonly occurring side effect of many commonly used chemotherapeutic agents, which in some cases may prevent cancer patients from being able to complete their treatment.

Cannabinoid based therapies have the potential to manage or even prevent pain associated with this syndrome.

Pre-clinical animal studies that investigate the modulation of the endocannabinoid system (endogenous cannabinoid pathway) are being conducted to better understand the mechanisms behind this phenomenon.

Five recent pre-clinical studies identified from Medline published between 2013 and 2016 were selected for review. All studies evaluated the effect of small-molecule agonists or antagonists on components of the endocannabinoid system in rats or mice, using cisplatin or paclitax-el-induced allodynia as a model of chemotherapy-induced neuropathic pain. Activation of the cannabinoid receptor-2 (CB-2) receptor by AM1710 blocked paclitaxel-induced mechanical and cold allodynia in one study.

Four studies investigating the activation of both cannabinoid receptor-1 (CB-1) and CB-2 receptors by dual-agonists (WIN55,21 and CP55,940), or by the introduction of inhibitors of endocannabinoid metabolisers (URB597, URB937, JZL184, and SA-57) showed reduction of chemotherapy-induced al-lodynia. In addition, their results suggest that anti-allodynic effects may also be mediated by additional receptors, including TRPV1 and 5-hydroxytryptamine (5-HT1A).

Pre-clinical studies demon-strate that the activation of endocannabinoid CB-1 or CB-2 receptors produces physiological effects in animal models, namely the reduction of chemotherapy-induced allodynia. These studies also provide in-sight into the biological mechanism behind the therapeutic utility of cannabis compounds in managing chemotherapy-induced neuropathic pain, and provide a basis for the conduct of future clinical studies in patients of this population.”

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Medical cannabis Q&A

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  • “1. What is medical cannabis?

The term “medical cannabis” is used to describe products derived from the whole cannabis plant or its extracts containing a variety of active cannabinoids and terpenes, which patients take for medical reasons, after interacting with and obtaining authorization from their health care practitioner.

  • 2. What are the main active ingredients?

The chemical ingredients of cannabis are called cannabinoids. The 2 main therapeutic ones are:

  •  A Tetrahydrocannabinol (THC) is a partial agonist of CB1 and CB2 receptors. It is psychoactive and produces the euphoric effect.
  •  B Cannabidiol (CBD) has a weak affinity for CB1 and CB2 receptors and appears to exert its activity by enhancing the positive effects of the body’s endogenous cannabinoids
 3. Why do patients take it?

Medical cannabis may be used to alleviate symptoms for a variety of conditions. It has most commonly been used in neuropathic pain and other chronic pain conditions. There is limited, but developing, clinical evidence surrounding its safety and efficacy, and it does not currently have an approved Health Canada indication.

  • 4. How do patients take it?

Cannabis can be smoked, vaporized, taken orally, sublingually, topically or rectally. Different routes of administration will result in different pharmacokinetic and pharmacodynamic properties of the drug.

  • 5. Is it possible to develop dependence on medical cannabis?

Yes, abrupt discontinuation after long-term use may result in withdrawal symptoms. Additionally, chronic use may result in psychological dependence.

  • 6. What is the difference between medical and recreational cannabis?

Patients taking cannabis for medical reasons generally use cannabinoids to alleviate symptoms while minimizing intoxication, whereas recreational users may be taking cannabis for euphoric effects. Medical cannabis is authorized by a prescriber who provides a medical document allowing individuals to obtain cannabis from a licensed producer or apply to Health Canada to grow their own, whereas recreational cannabis is currently obtained through illicit means.

  • 7. How can patients access cannabis for medical purposes?
  • 8. Does medical cannabis have a DIN?

Pharmacological cannabinoids such as Sativex (delta-9-tetrahydrocannabinol-cannabidiol) and Cesamet (nabilone) have been approved for specific indications by Health Canada, however, herbal medical cannabis has not gone through Health Canada’s drug review and approval process, nor does it have a Drug Identification Number (DIN) or Natural Product Number (NPN).

  • 9. Is medical cannabis covered through insurance?

Some insurance plans may cover medical cannabis. Check each patient’s individual plan for more details.

  • 10. What role can pharmacists play in medical cannabis?

Even though pharmacists are not dispensing medical cannabis at this time, it is important for them to understand how their patients may use and access medical cannabis in order to provide effective medication management. Pharmacists may provide counselling on areas such as contraindications, drug interactions, management of side effects, alternative therapies, potential addictive behaviour and appropriate use.

  • 11. Where can I find more information about medical cannabis?

You can find more information on Health Canada’s website:” https://www.canada.ca/en/health-canada/services/drugs-health-products/medical-use-marijuana/medical-use-marijuana.html

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5661684/

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Remote Ischemia Preconditioning Attenuates Blood-Spinal Cord Barrier Breakdown in Rats Undergoing Spinal Cord Ischemia Reperfusion Injury: Associated with Activation and Upregulation of CB1 and CB2 Receptors.

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“Remote ischemic preconditioning (RIPC) has protective effects on spinal cord ischemia reperfusion (I/R) injury, but the potential mechanisms remain unclear. In our study, the effects and underlying mechanisms of RIPC on blood-spinal cord barrier (BSCB) breakdown following I/R injury were investigated.

RIPC attenuated the motor dysfunction, BSCB disruption and downregulation of occludin after I/R injury, which were impaired by blocking CB1 and CB2 receptors. Moreover, RIPC upregulated the elevated perivascular expression of CB1 and CB2 receptors following I/R injury.

CONCLUSIONS:

These results indicated that RIPC, through activation and upregulation of CB1 and CB2 receptors, was involved in preserving the integrity of BSCB after spinal cord I/R injury.”

https://www.ncbi.nlm.nih.gov/pubmed/29130941

https://www.karger.com/Article/FullText/484460

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ACPA and JWH-133 modulate the vascular tone of superior mesenteric arteries through cannabinoid receptors, BKCa channels, and nitric oxide dependent mechanisms.

Pharmacological Reports

“Some cannabinoids, a family of compounds derived from Cannabis sativa (marijuana), have previously shown vasodilator effects in several studies, a feature that makes them suitable for the generation of a potential treatment for hypertension.

The mechanism underlying this vasodilator effect in arteries is still controversial. In this report, we explored how the synthetic cannabinoids ACPA (CB1-selective agonist) and JWH-133 (CB2-selective agonist) regulate the vascular tone of rat superior mesenteric arteries.

CB1 and CB2 receptor activation in superior mesenteric artery causes vasorelaxation by mechanisms involving BKCachannels and NO release.”

https://www.ncbi.nlm.nih.gov/pubmed/29128791

http://www.sciencedirect.com/science/article/pii/S1734114017300361?via%3Dihub

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Perinatal maternal high-fat diet induces early obesity and sex-specific alterations of the endocannabinoid system in white and brown adipose tissue of weanling rat offspring.

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“Perinatal maternal high-fat (HF) diet programmes offspring obesity. Obesity is associated with overactivation of the endocannabinoid system (ECS) in adult subjects, but the role of the ECS in the developmental origins of obesity is mostly unknown. The ECS consists of endocannabinoids, cannabinoid receptors (cannabinoid type-1 receptor (CB1) and cannabinoid type-2 receptor (CB2)) and metabolising enzymes.

We hypothesised that perinatal maternal HF diet would alter the ECS in a sex-dependent manner in white and brown adipose tissue of rat offspring at weaning in parallel to obesity development.

Maternal HF diet induced early obesity, white adipocyte hypertrophy and increased lipid accumulation in brown adipose tissue associated with sex-specific changes of the ECS’s components in weanling rats. In male pups, maternal HF diet decreased CB1 and CB2 protein in subcutaneous adipose tissue. In female pups, maternal HF diet increased visceral and decreased subcutaneous CB1. In brown adipose tissue, maternal HF diet increased CB1 regardless of pup sex. In addition, maternal HF diet differentially changed oestrogen receptor across the adipose depots in male and female pups.

The ECS and oestrogen signalling play an important role in lipogenesis, adipogenesis and thermogenesis, and we observed early changes in their targets in adipose depots of the offspring. The present findings provide insights into the involvement of the ECS in the developmental origins of metabolic disease induced by inadequate maternal nutrition in early life.”

https://www.ncbi.nlm.nih.gov/pubmed/29110748

https://www.cambridge.org/core/journals/british-journal-of-nutrition/article/perinatal-maternal-highfat-diet-induces-early-obesity-and-sexspecific-alterations-of-the-endocannabinoid-system-in-white-and-brown-adipose-tissue-of-weanling-rat-offspring/6BA3A77DE45A1537E0BC182E83EF07F0

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Characterization of endocannabinoids and related acylethanolamides in the synovial fluid of dogs with osteoarthritis: a pilot study.

 Image result for bmc veterinary research

“Cannabis-based drugs have been shown to be effective in inflammatory diseases.

A number of endocannabinoids including N- arachidonoylethanolamide (anandamide, AEA) and 2-arachidonyl glycerol (2-AG) with activity at the cannabinoidreceptors (CBR) CBR1 and CBR2, have been identified. Other structurally related endogenous fatty acid compounds such as oleoylethanolamide (OEA) and palmitoyl ethanolamide (PEA) have been identified in biological tissues.

These compounds do not bind to CBR but might be involved in facilitating the actions of directly acting endocannabinoids and thus are commonly termed “entourage” compounds due to their ability to modulate the endocannabinoid system.

The aim of this study was to evaluate the presence of endocannabinoids and entourage compounds in the synovial fluid of dogs with osteoarthritis subjected to arthrotomy of the knee joint. Cytokines and cytology were studied as well.

AEA, 2-AG, OEA and PEA were all present in the synovial fluid of arthritic knees and in the contralateral joints; in addition, a significant increase of OEA and 2AG levels were noted in SF from OA knees when compared to the contralateral joints.

The identification and quantification of endocannabinoids and entourage compounds levels in synovial fluids from dogs with OA of the knee is reported for the first time. Our data are instrumental for future studies involving a greater number of dogs. Cannabinoids represent an emerging and innovative pharmacological tool for the treatment of OA and further studies are warranted to evaluate the effectiveness of cannabinoids in veterinary medicine.”

https://www.ncbi.nlm.nih.gov/pubmed/29110674

“The ECS can be exploited as a potential therapeutic option for OA. We have demonstrated the presence of AEA, 2-AG, OEA and PEA in the SF of dogs with OA. Our data open the avenue to future studies involving a higher number of dogs and aimed at defining the role played by these compounds in OA of the dogs. Both plant-derived and synthetic agonists of CBRs represent an emerging and innovative pharmacological tool for the treatment of OA. ” https://bmcvetres.biomedcentral.com/articles/10.1186/s12917-017-1245-7

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Cannabinoid receptor 1/2 double-knockout mice develop epilepsy.

Epilepsia

“The endocannabinoid system has gained attention as an important modulator of activity in the central nervous system. Initial studies focused on cannabinoid receptor 1 (CB1), which is widely expressed in the brain, but recent work also implicates cannabinoidreceptor 2 (CB2) in modulating neuronal activity.

Both receptors are capable of reducing neuronal activity, generating interest in cannabinoid receptor agonists as potential anticonvulsants.

CB1 (Cnr1) and CB2 (Cnr2) single-knockout mice have been generated, with the former showing heightened seizure sensitivity, but not overt seizures. Given overlapping and complementary functions of CB1 and CB2 receptors, we queried whether double-knockout mice would show an exacerbated neurological phenotype.

Strikingly, 30% of double-knockout mice exhibited provoked behavioral seizures, and 80% were found to be epileptic following 24/7 video-electroencephalographic monitoring. Single-knockout animals did not exhibit seizures. These findings highlight the importance of the endocannabinoid system for maintaining network stability.”

https://www.ncbi.nlm.nih.gov/pubmed/29105060

http://onlinelibrary.wiley.com/doi/10.1111/epi.13930/abstract

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Parameters of the Endocannabinoid System as Novel Biomarkers in Sepsis and Septic Shock.

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“Sepsis represents a dysregulated immune response to infection, with a continuum of severity progressing to septic shock. This dysregulated response generally follows a pattern by which an initial hyperinflammatory phase is followed by a state of sepsis-associated immunosuppression.

Major challenges in improving sepsis care include developing strategies to ensure early and accurate identification and diagnosis of the disease process, improving our ability to predict outcomes and stratify patients, and the need for novel sepsis-specific treatments such as immunomodulation.

Biomarkers offer promise with all three of these challenges and are likely also to be the solution to determining a patient’s immune status; something that is critical in guiding effective and safe immunomodulatory therapy. Currently available biomarkers used in sepsis lack sensitivity and specificity, among other significant shortcomings.

The endocannabinoid system (ECS) is an emerging topic of research with evidence suggesting a ubiquitous presence on both central and peripheral tissues, including an intrinsic link with immune function. This review will first discuss the state of sepsis biomarkers and lack of available treatments, followed by an introduction to the ECS and a discussion of its potential to provide novel biomarkers and treatments.”

https://www.ncbi.nlm.nih.gov/pubmed/29104224

http://www.mdpi.com/2218-1989/7/4/55

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Maternal high-fat diet induces sex-specific endocannabinoid system changes in newborn rats and programs adiposity, energy expenditure and food preference in adulthood.

The Journal of Nutritional Biochemistry

“Early life inadequate nutrition triggers developmental adaptations and adult chronic disease.

Maternal high-fat (HF) diet promotes visceral obesity and hypothalamic leptin resistance in male rat offspring at weaning and adulthood.

Obesity is related to over active endocannabinoid system (ECS). The ECS consists mainly of endogenous ligands, cannabinoid receptors (CB1 and CB2), and the enzymes fatty acid anandamide hydrolase (FAAH) and monoacylglycerol lipase (MAGL).

We hypothesized that perinatal maternal HF diet would regulate offspring ECS in hypothalamus and brown adipose tissue (BAT) at birth, prior to visceral obesity development, and program food preference and energy expenditure of adult offspring.

In conclusion, maternal HF diet alters ECS components and energy metabolism targets in hypothalamus and BAT of offspring at birth, in a sex-specific manner, which may contribute for hyperphagia, food preference and higher adiposity later in life.”

https://www.ncbi.nlm.nih.gov/pubmed/29102876

http://www.sciencedirect.com/science/article/pii/S0955286317303042?via%3Dihub

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