Tag Archives: CB(1) and CB(2) receptors

Sativex-like Combination of Phytocannabinoids is Neuroprotective in Malonate-Lesioned Rats, an Inflammatory Model of Huntington’s Disease: Role of CB(1) and CB(2) Receptors.

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Abstract

“We have investigated whether a 1:1 combination of botanical extracts enriched in either Δ(9)-tetrahydrocannabinol (Δ(9)-THC) or cannabidiol (CBD), which are the main constituents of the cannabis-based medicine Sativex, is neuroprotective in Huntington’s disease (HD), using an experimental model of this disease generated by unilateral lesions of the striatum with the mitochondrial complex II inhibitor malonate. This toxin damages striatal neurons by mechanisms that primarily involve apoptosis and microglial activation. We monitored the extent of this damage and the possible preservation of the striatal parenchyma by treatment with a Sativex-like combination of phytocannabinoids using different histological and biochemical markers. Results were as follows: (i) malonate increased the volume of edema measured by in vivo NMR imaging and the Sativex-like combination of phytocannabinoids partially reduced this increase; (ii) malonate reduced the number of Nissl-stained cells, while enhancing the number of degenerating cells stained with FluoroJade-B, and the Sativex-like combination of phytocannabinoids reversed both effects; (iii) malonate caused a strong glial activation (i.e., reactive microglia labeled with Iba-1, and astrogliosis labeled with GFAP) and the Sativex-like combination of phytocannabinoids attenuated both responses; and (iv) malonate increased the expression of inducible nitric oxide synthase and the neurotrophin IGF-1, and both responses were attenuated after the treatment with the Sativex-like combination of phytocannabinoids. We also wanted to establish whether targets within the endocannabinoid system (i.e., CB(1) and CB(2) receptors) are involved in the beneficial effects induced in this model by the Sativex-like combination of phytocannabinoids. This we did using selective antagonists for both receptor types (i.e., SR141716 and AM630) combined with the Sativex-like phytocannabinoid combination. Our results indicated that the effects of this combination are blocked by these antagonists and hence that they do result from an activation of both CB(1) and CB(2) receptors. In summary, this study provides preclinical evidence in support of a beneficial effect of the cannabis-based medicine Sativex as a neuroprotective agent capable of delaying signs of disease progression in a proinflammatory model of HD, which adds to previous data obtained in models priming oxidative mechanisms of striatal injury. However, the interest here is that, in contrast with these previous data, we have now obtained evidence that both CB(1) and CB(2) receptors appear to be involved in the effects produced by a Sativex-like phytocannabinoid combination, thus stressing the broad-spectrum properties of Sativex that may combine activity at the CB(1) and/or CB(2) receptors with cannabinoid receptor-independent actions.”

http://www.ncbi.nlm.nih.gov/pubmed/22860209

Neuroprotective effects of phytocannabinoid-based medicines in experimental models of Huntington’s disease.

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Abstract

“We studied whether combinations of botanical extracts enriched in either Δ(9)-tetrahydrocannabinol (Δ(9)-THC) or cannabidiol (CBD), which are the main constituents of the cannabis-based medicine Sativex, provide neuroprotection in rat models of Huntington’s disease (HD). We used rats intoxicated with 3-nitropropionate (3NP) that were given combinations of Δ(9)-THC- and CBD-enriched botanical extracts. The issue was also studied in malonate-lesioned rats. The administration of Δ(9)-THC- and CBD-enriched botanical extracts combined in a ratio of 1:1 as in Sativex attenuated 3NP-induced GABA deficiency, loss of Nissl-stained neurons, down-regulation of CB(1) receptor and IGF-1 expression, and up-regulation of calpain expression, whereas it completely reversed the reduction in superoxide dismutase-1 expression. Similar responses were generally found with other combinations of Δ(9)-THC- and CBD-enriched botanical extracts, suggesting that these effects are probably related to the antioxidant and CB(1) and CB(2) receptor-independent properties of both phytocannabinoids. In fact, selective antagonists for both receptor types, i.e., SR141716 and AM630, respectively, were unable to prevent the positive effects on calpain expression caused in 3NP-intoxicated rats by the 1:1 combination of Δ(9)-THC and CBD. Finally, this combination also reversed the up-regulation of proinflammatory markers such as inducible nitric oxide synthase observed in malonate-lesioned rats. In conclusion, this study provides preclinical evidence in support of a beneficial effect of the cannabis-based medicine Sativex as a neuroprotective agent capable of delaying disease progression in HD, a disorder that is currently poorly managed in the clinic, prompting an urgent need for clinical trials with agents showing positive results in preclinical studies.”

http://www.ncbi.nlm.nih.gov/pubmed/21674569

Antidepressant-like effect of Δ9-tetrahydrocannabinol and other cannabinoids isolated from Cannabis sativa L

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“The antidepressant action of cannabis as well as the interaction between antidepressants and the endocannabinoid system has been reported. This study was conducted to assess the antidepressant-like activity of Δ9-THC and other cannabinoids… Results of this study show that Δ9-THC and other cannabinoids exert antidepressant-like actions, and thus may contribute to the overall mood-elevating properties of cannabis.”

“Cannabis sativa L. is one of the most widely used plants for both recreational and medicinal purposes. To date a total of 525 natural constituents covering several chemical classes have been isolated and identified from C. sativa. The cannabinoids belong to the chemical class of terpenophenolics, of which 85 have been uniquely identified in cannabis, including the most psychoactive cannabinoid, Δ9-tetrahydrocannabinol (Δ9-THC). The most common natural plant cannabinoids (phytocannabinoids) are: Δ9-THC, cannabidiol (CBD), cannabigerol (CBG), cannabichromene (CBC), and cannabinol (CBN). Several of the identified cannabinoids are both chemically and pharmacologically poorly characterized due to insufficient isolated amounts; however, the pharmacology of Δ9-THC has been widely studied, and it is regarded as the main psychoactive constituent of cannabis.”

“The psychological and physiological effects of cannabis have been extensively characterized, including euphoria, analgesia, sedation, memory and cognitive impairment, appetite stimulation, and anti-emesis. Most of these effects have been primarily attributed to Δ9-THC. Major advances in the field of cannabinoid research were achieved following the unraveling of the molecular mechanism underlying the actions of Δ9-THC and the discovery of the endocannabinoid system. The endocannabinoid system is regarded as a neuromodulator, and is comprised of cannabinoid receptors (primarily CB1 and CB2 receptors), their endogenous ligands, and enzymes responsible for the synthesis and metabolism of these ligands.”

“In addition to the established effects of cannabis, it is well recognized that mood elevation is one of the components of the complex experience elicited by cannabis. Much of our knowledge regarding cannabis effect on mood and anxiety is based on individual reports following cannabis use for medicinal or recreational purposes. Several anecdotal reports describe the antidepressant effect of cannabis, with patients confirming beneficial outcomes from its use in primary or secondary depressive disorders…”

“In conclusion, our results show that phytocannabinoids, including Δ9-THC, CBD, and CBC, exert antidepressant-like actions in animal models of behavioral despair. The exact mechanism underlying such activity is still unclear and confounded by the fact that these compounds have varying binding profiles to the established cannabinoid CB1 as well as to non CB1 receptors. The results support the effect of phytocannabinoids on mood disorders and provide potential leads for further studies.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2866040/

Antidepressant-like effects of cannabidiol in mice: possible involvement of 5-HT1A receptors

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 “Extracts of the Cannabis sativa plant elicit in humans a complex subjective experience that includes euphoria, heightened sensitivity to external stimuli and relaxation. This plant contains more than 400 different compounds, of which 66 are termed cannabinoids. Δ9-tetrahydrocannabinol (Δ9-THC), one of the major constituents of C. sativa extracts is thought to account for most of the effects of cannabis through the activation of cannabinoid CB1 receptors in the brain….The major endogenous agonists of the CB1 receptor are anandamide and 2-arachidonoyl glycerol, referred to as endocannabinoids…”

“It has recently been suggested that the endocannabinoid system may be involved in the pathophysiology of depression. This is supported by several pieces of evidence showing that endocannabinoids and CB1 receptors are widely distributed in brain areas that are often related to affective disorders and that their expression is regulated by antidepressant drugs. Moreover, administration of inhibitors of anandamide uptake or metabolism, as well as CB1 receptor agonists induces antidepressant-like effects in different animal models. In accordance with these preclinical results, many patients report benefits from cannabis use in depressive syndromes…”

“Cannabidiol (CBD) is a non-psychotomimetic compound from Cannabis sativa that induces anxiolytic- and antipsychotic-like effects in animal models. Effects of CBD may be mediated by the activation of 5-HT1A receptors. As 5-HT1A receptor activation may induce antidepressant-like effects, the aim of this work was to test the hypothesis that CBD would have antidepressant-like activity in mice as assessed by the forced swimming test. We also investigated if these responses depended on the activation of 5-HT1A receptors and on hippocampal expression of brain-derived neurotrophic factor (BDNF).”

“Conclusion and implications:

CBD induces antidepressant-like effects comparable to those of imipramine. These effects of CBD were probably mediated by activation of 5-HT1A receptors.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2823358/

A possible role for the endocannabinoid system in the neurobiology of depression

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“The present review synthetically describes the currently advanced hypotheses for a neurobiological basis of depression, ranging from the classical monoaminergic to the more recent neurotrophic hypothesis. Moreover, the Authors review the available preclinical and clinical evidence suggesting a possible role for the endocannabinoid system in the physiopathology of depression. Indeed, in spite of the reporting of conflicting results, the pharmacological enhancement of endocannabinoid activity at the CB1 cannabinoid receptor level appears to exert an antidepressant-like effect in some animal models of depression. On the contrary, a reduced activity of the endogenous cannabinoid system seems to be associated with the animal model of depression, namely the chronic mild stress model. Moreover, a few studies have reported an interaction of antidepressants with the endocannabinoid system. “

“The endocannabinoid system”

“A detailed description of the endocannabinoid system is beyond the scope of this paper. Thus, in this section we briefly describe those components of the endocannabinoid system that act as targets for the pharmacological interventions aimed at determining the activity of the endocannabinoid system.”

“The term “endocannabinoid system” refers to the recently discovered neuromodulator system comprising cannabinoid receptors (which represent the receptors of Tetrahydrocannabinol (THC), the major active component of cannabis) and their endogenous ligands.”

“To date, two types of cannabinoid receptors have been identified: CB1 and CB2 receptors. These receptors belong to the superfamily of G protein coupled receptors, the CB1 receptor is widely distributed in the terminals of neurons, while the CB2 receptor is extensively expressed throughout the immune system. However, it has recently been reported that these receptors are present also in the brain.”

“No clinical trials carried out using cannabinoids in the treatment of affective disorders have been published to date, although anecdotal reports have described both antidepressant and antimanic properties of cannabis.”

“Indeed, pharmacological manipulations of the endocannabinoid system have elicited antidepressant-like effects in animal models of depression. Moreover, some animal models of depression seem to be associated to alterations in the endocannabinod system.”

“Although no clinical trials performed using cannabinoids in the treatment of affective disorders have been published to date, anecdotal reports have described both antidepressant and antimanic properties of cannabis”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2169225/

Intrathecal Administration of the Cannabinoid 2 Receptor Agonist JWH015 Can Attenuate Cancer Pain and Decrease mRNA Expression of the 2B Subunit of N-Methyl-d-Aspartic Acid

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“Pain has a negative impact on the quality of life in cancer patients…

…we hypothesized that a cannabinoid receptor agonist might be a novel therapy for cancer pain. Taking into consideration the side effects of a CB1 receptor agonist (which limits their clinical application), we chose a CB2 receptor agonist to investigate its effect in cancer pain…

 Recent clinical trials have demonstrated that cannabinoids may have significant positive effects in refractory chronic and cancer pain. The cannabinoids are thought to exert most of their effects by binding to G protein–coupled cannabinoid receptors, which include 2 cloned metabotropic receptors: cannabinoid (CB)1 and CB2…

CONCLUSION: These data indicated that intrathecal administration of cannabinoid receptor agonists might relieve cancer pain… These results also suggested that cannabinoids might be a useful alternative or adjunct therapy for relieving cancer pain.

The use of a CB2 receptor agonist could be a novel option for treatment of cancer pain.”

 

 http://www.anesthesia-analgesia.org/content/113/2/405.long

Increasing 2-arachidonoyl glycerol signaling in the periphery attenuates mechanical hyperalgesia in a model of bone cancer pain

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“Metastatic and primary bone cancers are usually accompanied by severe pain that is difficult to manage. In light of the adverse side effects of opioids, manipulation of the endocannabinoid system may provide an effective alternative for the treatment of cancer pain…

These data extend our previous findings with anandamide in the same model and suggest that the peripheral endocannabinoid system is a promising target for the management of cancer pain.

Taken together, the data demonstrate that peripheral 2-AG signaling may be a significant target to exploit for the management of cancer pain. In contrast to AEA, which inhibits nociception through CB1 receptors… Dual pharmacological modulation of peripheral AEA and 2-AG signaling that directly and indirectly affects DRG neurons may be a novel approach to reducing cancer pain without the side effects…”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3104059/

 

CB1 and CB2 receptor agonists promote analgesia through synergy in a murine model of tumor pain

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“Pain associated with cancer and tumor growth is often difficult to manage.”

“Cannabis sativa has a long history of use for management of pain.”

“In light of the adverse side effects of opioids, cannabinoid (CB) receptor agonists may provide an effective alternative for the treatment of cancer pain. The present study examined the potency and efficacy of synthetic CB1 and CB2 receptor agonists in a murine model of tumor pain.”

“Co-administering both CB receptor agonists attenuated mechanical hyperalgesia through a synergistic mechanism.”

 

“Together these data support the use of combined CB1 and CB2 receptor agonists in the development of strategies for the treatment of tumor related pain.”

“These data extend our previous findings that the peripheral cannabinoid receptors are a promising target for the management of cancer pain and mixed cannabinoid receptor agonists may have a therapeutic advantage over selective agonists.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3155626/

Cannabinoids and omega-3/6 endocannabinoids as cell death and anticancer modulators.

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“Cannabinoids-endocannaboids are possible preventatives of common diseases including cancers. Cannabinoid receptors (CB(½), TRPV1) are central components of the system. Many disease-ameliorating effects of cannabinoids-endocannabinoids are receptor mediated, but many are not, indicating non-CBR signaling pathways.

Cannabinoids-endocannabinoids are anti-inflammatory, anti-proliferative, anti-invasive, anti-metastatic and pro-apoptotic in most cancers, in vitro and in vivo in animals.

They signal through p38, MAPK, JUN, PI3, AKT, ceramide, caspases, MMPs, PPARs, VEGF, NF-κB, p8, CHOP, TRB3 and pro-apoptotic oncogenes (p53,p21 waf1/cip1) to induce cell cycle arrest, autophagy, apoptosis and tumour inhibition. Paradoxically they are pro-proliferative and anti-apoptotic in some cancers. Differences in receptor expression and concentrations of cannabinoids in cancer and immune cells can elicit anti- or pro-cancer effects through different signal cascades (p38MAPK or PI3/AKT).

Similarities between effects of cannabinoids-endocannabinoids, omega-3 LCPUFA and CLAs/CLnAs as anti-inflammatory, antiangiogenic, anti-invasive anti-cancer agents indicate common signaling pathways.

Evidence in vivo and in vitro shows EPA and DHA can form endocannabinoids that: (i) are ligands for CB(½) receptors and possibly TRPV-1, (ii) have non-receptor mediated bioactivity, (iii) induce cell cycle arrest, (iii) increase autophagy and apoptosis, and (iv) augment chemotherapeutic actions in vitro. They can also form bioactive, eicosanoid-like products that appear to be non-CBR ligands but have effects on PPARs and NF-kB transcription factors. The use of cannabinoids in cancer treatment is currently limited to chemo- and radio-therapy-associated nausea and cancer-associated pain apart from one trial on brain tumours in patients. Further clinical studies are urgently required to determine the true potential of these intriguing, low toxicity compounds in cancer therapy. Particularly in view of their synergistic effects with chemotherapeutic agents similar to that observed for n-3 LCPUFA.”  https://www.ncbi.nlm.nih.gov/pubmed/23103355

http://www.sciencedirect.com/science/article/pii/S0163782712000537

[Cannabinoids in the control of pain].

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Abstract

“Hemp (Cannabis sativa L.) has been used since remotes ages as a herbal remedy. Only recently the medical community highlighted the pharmacological scientific bases of its effects. The most important active principle, Delta-9-tetrahydrocannabinol, was identified in the second half of the last century, and subsequently two receptors were identified and cloned: CB1 that is primarily present in the central nervous system, and CB2 that is present on the cells of the immune system. Endogenous ligands, called endocannabinoids, were characterized. The anandamide was the first one to be discovered. The effectiveness of the cannabinoids in the treatment of nausea and vomit due to anti-neoplastic chemotherapy and in the wasting-syndrome during AIDS is recognized. Moreover, the cannabinoids are analgesic, and their activity is comparable to the weak opioids. Furthermore, parallels exist between opioid and cannabinoid receptors, and evidence is accumulating that the two systems sometimes may operate synergistically. The interest of the pharmaceutical companies led to the production of various drugs, whether synthetic or natural derived. The good ratio between the polyunsatured fatty acids omega-3 and omega-6 of the oil of Cannabis seeds led to reduction of the phlogosis and an improvement of the pain symptoms in patients with chronic musculo-skeletal inflammation.”

http://www.ncbi.nlm.nih.gov/pubmed/19388223