“These data show that cannabinoids have potent antinociceptive effects through direct actions in the spinal dorsal horn of nociceptive pathway. This suggests that intrathecally administered cannabinoids may offer hopeful strategies for the treatment of diabetic neuropathic pain.”
Tag Archives: agonists
Opioid and cannabinoid synergy in a mouse neuropathic pain model.
“Clinical studies have reported that pan-cannabinoid receptor agonists may have efficacy in neuropathic pain states and that this might be enhanced by co-administration with opioids. While cannabinoid-opioid analgesic synergy has been demonstrated in animal models of acute pain, it has not been examined in neuropathic pain models. We examined the effect of combination treatment with cannabinoid and opioid receptor agonists on allodynia and side-effects in a nerve injury induced neuropathic pain model.
These findings indicate that combination administration of non-selective opioid and cannabinoid receptor agonists synergistically reduces nerve injury induced allodynia, while producing side-effects in an additive manner. This suggests that combination treatment has an improved anti-allodynic potency and therapeutic index in a neuropathic pain model.”
Pharmacological activation of cannabinoid 2 receptor attenuates inflammation, fibrogenesis, and promotes re-epithelialization during skin wound healing.
“Previous studies showed that cannabinoid 2 (CB2) receptor is expressed in multiple effector cells during skin wound healing. Meanwhile, its functional involvement in inflammation, fibrosis, and cell proliferation in other organs and skin diseases implied CB2 receptor might also regulate skin wound healing.
These results, taken together, indicate that activating CB2 receptor could ameliorate wound healing by reducing inflammation, accelerating re-epithelialization, and attenuating scar formation.
Thus, CB2 receptor agonist might be a novel perspective for skin wound therapy.”
RNA-seq analysis of delta -9-tetrahydrocannabinol-treated T cells reveals altered gene expression profiles that regulate immune response and cell proliferation.
“Marijuana has drawn significant public attention and concern both for its medicinal and recreational use. Δ9-tetrahydrocannabinol (THC), which is the main bioactive component in marijuana, has also been shown to possess potent anti-inflammatory properties by virtue of its ability to activate cannabinoid receptor-2 (CB-2) expressed on immune cells.
In this study, we used RNA-seq to quantify the transcriptomes and transcript variants that are differentially regulated by THC in super antigen-activated lymph node cells and CD4+ T cells. We found that the expressions of many transcripts were altered by THC in both total lymph node cells and CD4+ T cells. Furthermore, the abundance of many miRNA precursors and long non-coding RNAs was dramatically altered in THC treated mice. For example, the expression of miR-17/92 cluster and miR-374b/421 cluster was down regulated by THC. On the other hand miR-146a which has been shown to induce apoptosis was up regulated by THC. Long non-coding RNAs that are expressed from the opposite strand of CD27 and Appbp2 were induced by THC.
In addition, THC treatment also caused alternative promoter usage and splicing. The functions of those altered transcripts were mainly related to immune response and cell proliferation.”
Estradiol impacts the endocannabinoid system in female rats to influence behavioral and structural responses to cocaine.
“Compared with men, women show enhanced responses to drugs of abuse, and consequently are thought to be more vulnerable to addiction.
The ovarian hormone estradiol has emerged as a key facilitator in the heightened development of addiction in females. These actions of estradiol appear mediated by estrogen receptor (ER) activation of metabotropic glutamate receptor type 5 (mGluR5). However, the downstream effectors of this ER/mGluR5 signaling pathway are unknown.
Here we investigate whether cannabinoid 1 receptor (CB1R) activation is a part of the mechanism whereby estradiol influences behavioral and synaptic correlates of addiction.
Following repeated cocaine administration, estradiol-treated ovariectomized rats exhibited both sensitized locomotor responses and decreases in the dendritic spine density of nucleus accumbens core medium-spiny neurons in comparison to oil-treated controls. Both effects of estradiol were blocked by AM251, a CB1R inverse agonist.
These results indicate that part of the signaling mechanism through which estradiol impacts behavioral and synaptic correlates of addiction in female rats requires activation of CB1Rs.”
Cannabinoid 2 (CB2) receptor agonism reduces lithium chloride-induced vomiting in Suncus murinus and nausea-induced conditioned gaping in rats.
“We aimed to investigate the potential anti-emetic and anti-nausea properties of targeting the cannabinoid 2 (CB2) receptor.
We investigated the effect of the selective CB2 agonist, HU-308, on lithium chloride- (LiCl) induced vomiting in Suncus murinus (S. murnius) and conditioned gaping (nausea-induced behaviour) in rats.
These findings are the first to demonstrate the ability of a selective CB2 receptor agonist to reduce nausea in animal models, indicating that targeting the CB2 receptor may be an effective strategy, devoid of psychoactive effects, for managing toxin-induced nausea and vomiting.”
Gastric acid inhibitory and gastric protective effects of Cannabis and cannabinoids.
“Cannabis sativa has long been known for its psychotropic effect. Only recently with the discovery of the cannabinoid receptors, their endogenous legends and the enzymes responsible for their synthesis and degradation, the role of this ‘endocannabinoid system’ in different pathophysiologic processes is beginning to be delineated.
There is evidence that CB1 receptor stimulation with synthetic cannabinoids or Cannabis sativa extracts rich in Δ9-tetrahydrocannabinol inhibit gastric acid secretion in humans and experimental animals.
This is specially seen when gastric acid secretion is stimulated by pentagastrin, carbachol or 2-deoxy-d-glucose.
Cannabis and/or cannabinoids protect the gastric mucosa against noxious challenge with non-steroidal anti-inflammatory drugs, ethanol as well as against stress-induced mucosal damage.
Cannabis/cannabinoids might protect the gastric mucosa by virtue of its antisecretory, antioxidant, anti-inflammatory, and vasodilator properties.”
Cannabinoid receptor-2 stimulation suppresses neuroinflammation by regulating microglial M1/M2 polarization through the cAMP/PKA pathway in an experimental GMH rat model.
“Excessive inflammatory responses are involved in secondary brain injury during germinal matrix hemorrhage (GMH). The process of microglial polarization to the pro-inflammatory M1 or anti-inflammatory M2 phenotypes is considered to occur in a major immunomodulatory manner during brain inflammation.
We previously found that cannabinoid receptor-2 (CB2R) stimulation attenuated microglial accumulation and brain injury following experimental GMH.
Herein, we investigated the effects of CB2R stimulation on neuroinflammation after experimental GMH and the potential mechanisms that mediate M1/M2 microglial phenotype regulation.
This is the first study to propose that promotion of microglial M2 polarization through the cAMP/PKA pathway participates in the CB2R-mediated anti-inflammatory effects after GMH induction.
The results will help to further understand the mechanisms that underlie neuroprotection by CB2R in GMH and promote clinical translational research for CB2R agonists.”
Clinical Effects of Synthetic Cannabinoid Receptor Agonists Compared with Marijuana in Emergency Department Patients with Acute Drug Overdose.
“Synthetic cannabinoid receptor agonists (SCRAs) are heterogeneous compounds originally intended as probes of the endogenous cannabinoid system or as potential therapeutic agents.
In the first clinical study comparing the adverse effects of SCRA overdose vs. marijuana controls in an ED population, we found that SCRA overdoses had significantly pronounced neurotoxicity and cardiotoxicity compared with marijuana.”
Protocol to Study β-Arrestin Recruitment by CB1 and CB2 Cannabinoid Receptors.
“Cannabinoid CB1 and CB2 receptors are G-protein-coupled receptors (GPCRs) that recruit β-arrestins upon activation by (partial) agonists. β-Arrestin recruitment is induced by phosphorylation of their C-terminal tails, and is associated with the termination of GPCR signaling; yet, it may also activate cellular signaling pathways independent of G-proteins. Here, we describe a detailed protocol to characterize the potency and efficacy of ligands to induce or inhibit β-arrestin recruitment to the human CB1 and CB2 receptors, by using the PathHunter(®) assay. The latter is a cellular assay that can be performed in plates with 384-wells. The PathHunter(®) assay makes use of β-galactosidase complementation, and has a chemiluminescent readout. We used this assay to characterize a set of reference ligands (both agonists and antagonists) on human CB1 and CB2 receptors.”