Synthetic Cannabinoids.

“Synthetic cannabinoids (SCBs), also known under the brand names of “Spice,” “K2,” “herbal incense,” “Cloud 9,” “Mojo” and many others, are becoming a large public health concern due not only to their increasing use but also to their unpredictable toxicity and abuse potential. There are many types of SCBs, each having a unique binding affinity for cannabinoid receptors.

Although both Δ-tetrahydrocannabinol (THC) and SCBs stimulate the same receptors, cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2), studies have shown that SCBs are associated with higher rates of toxicity and hospital admissions than is natural cannabis.

This is likely due to SCBs being direct agonists of the cannabinoidreceptors, whereas THC is a partial agonist.

Furthermore, the different chemical structures of SCBs found in Spice or K2 may interact in unpredictable ways to elicit previously unknown, and the commercial products may have unknown contaminants.

The largest group of users is men in their 20s who participate in polydrug use.

The most common reported toxicities with SCB use based on studies using Texas Poison Control records are tachycardia, agitation and irritability, drowsiness, hallucinations, delusions, hypertension, nausea, confusion, dizziness, vertigo and chest pain. Acute kidney injury has also been strongly associated with SCB use.

Treatment mostly involves symptom management and supportive care.

More research is needed to identify which contaminants are typically found in synthetic marijuana and to understand the interactions between different SBCs to better predict adverse health outcomes.”

Sperm Release from the Oviductal Epithelium Depends on Ca2+ Influx Upon Activation of CB1 and TRPV1 by Anandamide.

“The oviduct acts as a functional sperm reservoir in many mammalian species. Both binding and release of spermatozoa from the oviductal epithelium are mainly modulated by sperm capacitation. Several molecules from oviductal fluid are involved in the regulation of sperm function.

Anandamide is a lipid mediator involved in reproductive physiology. Previously, we demonstrated that anandamide, through activation of the cannabinoid receptor type 1 (CB1), promotes sperm release from bovine oviductal epithelial cells, and through CB1 and the transient receptor potential vanilloid 1 (TRPV1), induces sperm capacitation.

Our results also suggest that a phospholypase C (PLC) might mediate the activation of CB1 and TRPV1 in sperm release from the bovine oviduct.

Therefore, our findings indicate that anandamide, through CB1 and TRPV1 activation, is involved in sperm release from the oviductal reservoir. An increase of sperm Ca2+ levels and the PLC activation might be involved in anandamide signaling pathway. ”

http://www.ncbi.nlm.nih.gov/pubmed/26129689

Cannabinoid receptor-interacting protein 1a modulates CB1 receptor signaling and regulation.

“Cannabinoid CB1 receptors (CB1Rs) mediate the presynaptic effects of endocannabinoids in the central nervous system (CNS) and most behavioral effects of exogenous cannabinoids.

Cannabinoid receptor-interacting protein 1a (CRIP1a) binds to the CB1R C-terminus and can attenuate constitutive CB1R-mediated inhibition of Ca(2+) channel activity.

We now demonstrate cellular colocalization of CRIP1a at neuronal elements in the CNS and show that CRIP1a inhibits both constitutive and agonist-stimulated CB1R-mediated guanine nucleotide-binding regulatory protein (G-protein) activity.

These results confirm that CRIP1a inhibits constitutive CB1R activity and demonstrate that CRIP1a can also inhibit agonist-stimulated CB1R signaling and downregulation of CB1Rs. Thus, CRIP1a appears to act as a broad negative regulator of CB1R function.”

http://www.ncbi.nlm.nih.gov/pubmed/25657338

Modulatory effects by CB1 receptors on rat spinal locomotor networks after sustained application of agonists or antagonists.

“Sustained administration of cannabinoid agonists acting on neuronal CB1 receptors (CB1Rs) are proposed for treating spasticity and chronic pain…

Our data suggest that CB1Rs may control the circuit gateway regulating the inflow of sensory afferent inputs into the locomotor circuits, indicating a potential site of action for restricting peripheral signals disruptive for locomotor activity.”

Colocalization of cannabinoid receptor 1 with somatostatin and neuronal nitric oxide synthase in rat brain hippocampus.

“Somatostatin (SST), a growth hormone inhibitory peptide, is expressed in different parts of the brain and functions as a neurotransmitter and neuromodulator. In the central nervous system (CNS), SST inhibits Ca2+ influx and regulates neuronal excitability in the hippocampus, the brain region which plays a major role in seizure, as well as cognitive and memory function.

Much like SST, cannabinoid receptor 1 (CB1 receptor) is also widely distributed in the CNS, associated with memory function ad exerts inhibitory effects on seizure.

It is unknown whether overlapping functional activities of SST and CB1 receptor are also associated with coexpression in the hippocampus.

In the present study, we determined the colocalization between SST and CB1 receptor in adult rat brain hippocampus. In the CNS, the majority of SST positive interneurons coexpress neuronal nitric oxide synthase (nNOS). Accordingly, colocalization studies were also performed to determine whether nNOS positive neurons display comparable colocalization with CB1 receptor.

The findings suggested that SST and nNOS are expressed in most interneurons whereas CB1 receptor is present in both interneurons and projection neurons in hippocampal regions. The distinct neuronal populations either expressing CB1 receptor, SST and nNOS alone or colocalization were observed in a region specific manner.

Taken together, the observations described here anticipate the possibility of crosstalk between somatostatin subtypes and CB1 receptor in regulation of physiological activities in the hippocampus.”

http://www.ncbi.nlm.nih.gov/pubmed/26115586

An ultra-low dose of tetrahydrocannabinol provides cardioprotection.

“Tetrahydrocannabinol (THC), the major psychoactive component of marijuana, is a cannabinoid agonist that exerts its effects by activating at least two specific receptors (CB1 and CB2) that belong to the seven transmembrane G-protein coupled receptor (GPCR) family.

Both CB1 and CB2 mRNA and proteins are present in the heart.

THC treatment was beneficial against hypoxia in neonatal cardiomyocytes in vitro.

We also observed a neuroprotective effect of an ultra low dose of THC when applied to mice before brain insults.

The present study was aimed to test and characterize the cardioprotective effects of a very low dose of THC…

All protocols of THC administration were found to be beneficial.

CONCLUSION:

A single ultra low dose of THC before ischemia is a safe and effective treatment that reduces myocardial ischemic damage.”

http://www.ncbi.nlm.nih.gov/pubmed/23537701

The endocannabinoid anandamide during lactation increases body fat content and CB1 receptor levels in mice adipose tissue.

“Type 1 cannabinoid receptors (CB1R) modulate energy balance; thus, their premature activation may result in altered physiology of tissues involved in such a function.

Activation of CB1R mainly occurs after binding to the endocannabinoid Anandamide (AEA).

The objective of this study was to evaluate the effects of AEA treatment during lactation on epididymal and body fat content, in addition to CB1R protein level at weaning.

This in vivo study shows for the first time that a progressive increase in body fat accumulation can be programmed in early stages of life by oral treatment with the endocannabinoid AEA, a fact associated with an increased amount of epididymal fat pads and a higher expression of CB1R in this tissue.”

http://www.ncbi.nlm.nih.gov/pubmed/26098446

Topical cannabinoid receptor 1 agonist attenuates the cutaneous inflammatory responses in oxazolone-induced atopic dermatitis model.

“This study was performed to investigate the effects of CBR agonists on skin inflammation, using acute and chronic inflammation animal models.

All of the results suggest that topical application of CB1R-specific agonist can be beneficial for alleviating the inflammatory symptoms in chronic skin diseases, including atopic dermatitis.”

http://www.ncbi.nlm.nih.gov/pubmed/26095080

CB1 cannabinoid receptor antagonist attenuates left ventricular hypertrophy and Akt-mediated cardiac fibrosis in experimental uremia.

“Cannabinoid receptor type 1 (CB1R) plays an important role in the development of myocardial hypertrophy and fibrosis-2 pathological features of uremic cardiomyopathy. However, it remains unknown whether CB1R is involved in the pathogenesis of uremic cardiomyopathy.

Here, we aimed to elucidate the role of CB1R in the development of uremic cardiomyopathy via modulation of Akt signalling…

CB1R inhibition exerts anti-fibrotic effects via modulation of Akt signaling in H9c2 myofibroblasts.

Therefore, the development of drugs targeting CB1R may have therapeutic potential in the treatment of uremic cardiomyopathy.”

Cannabidiol causes endothelium-dependent vasorelaxation of human mesenteric arteries via CB1 activation.

“The protective effects of cannabidiol (CBD) have been widely shown in preclinical models and have translated into medicines for the treatment of multiple sclerosis and epilepsy. However, the direct vascular effects of CBD in humans are unknown.

CONCLUSION:

This study shows, for the first time, that CBD causes vasorelaxation of human mesenteric arteries via activation of CB1 and TRP channels, and is endothelium- and nitric oxide-dependent.”

http://www.ncbi.nlm.nih.gov/pubmed/26092099