“Previously, we presented electrophysiological evidence for presence in mice brain slices of functional cannabinoid type I receptors (CB1Rs) within the laterodorsal tegmentum (LDT), a brain stem nucleus critical in control of arousal and rapid eye movement (REM) sleep. Further, using pharmacological agents, we provided data suggestive of the endogenous presence of cannabinoids (CBs) acting at LDT CB1Rs. However, in those studies, we were unable to identify the type(s) of CB ligands endogenously present in the LDT, and this information has not been provided elsewhere. Accordingly, we used the highly-sensitive liquid chromatography/mass spectrometry (LC-MS) method to determine whether N-arachidonoylethanolamide (Anandamide or AEA) and 2-arachidonyl glycerol (2-AG), which are both endogenous CB ligands acting at CB1Rs, are present in the LDT. Mice brain tissue samples of the LDT were assayed using ion trap LC-MS in selected ion monitoring mode. Chromatographic analysis and product-ion MS scans identified presence of the CBs, AEA and 2-AG, from LDT mouse tissue. Data using the LC-MS method show that AEA and 2-AG are endogenously present within the LDT and when coupled with our electrophysiological findings, lead to the suggestion that AEA and 2-AG act at electropharmacologically-demonstrated CB1Rs in this nucleus. Accordingly, AEA and 2-AG likely play a role in processes governed by the LDT, including control of states of cortical gamma band activity seen in alert, aroused states, as well as cortical and motor activity characteristic of REM sleep.” https://www.ncbi.nlm.nih.gov/pubmed/28404451]]>
Tag Archives: CB1
Enhancement of Anandamide-Mediated Endocannabinoid Signaling Corrects Autism-Related Social Impairment
“We recently uncovered a signaling mechanism by which the endocannabinoid anandamide mediates the action of oxytocin, a neuropeptide that is crucial for social behavior, to control social reward. Oxytocin signaling has been implicated in autism spectrum disorder (ASD), and social reward is a key aspect of social functioning that is thought to be disrupted in ASD. Therefore, as a proof of principle for the core component of ASD—social impairment—we tested an endocannabinoid-enhancing compound on two widely studied mouse models of ASD, the BTBR and fmr1−/− (model of Fragile X Syndrome).
Remarkably, we found that FAAH blockade completely reversed the social impairment in both mouse models. CB1 receptor blockade prevented the prosocial action of FAAH inhibition in BTBR mice.
The results suggest that increasing anandamide activity at CB1 receptors improves ASD-related social impairment and identify FAAH as a novel therapeutic target for ASD.
In conclusion, the present study provides new insights into the role of endocannabinoid signaling in social behavior and validates FAAH as a novel therapeutic target for the social impairment of ASD.”
Dual therapy targeting the endocannabinoid system prevents experimental diabetic nephropathy.
“The endocannabinoid system has been implicated in the pathogenesis of diabetic nephropathy (DN). We investigated the effect of combined therapy with AM6545, a ‘peripherally’ restricted cannabinoid receptor type 1 (CB1R) neutral antagonist, and AM1241, a cannabinoid receptor type 2 (CB2R) agonist, in experimental DN.
RESULTS.:
Single treatment with either AM6545 or AM1241 alone reduced diabetes-induced albuminuria and prevented nephrin loss both in vivo and in vitro in podocytes exposed to glycated albumin. Dual therapy performed better than monotherapies, as it abolished albuminuria, inflammation, tubular injury and markedly reduced renal fibrosis. Converging anti-inflammatory mechanisms provide an explanation for this greater efficacy as dual therapy abolished diabetes-induced renal monocyte infiltration and M1/M2 macrophage imbalance in vivo and abrogated the profibrotic effect of M1 macrophage-conditioned media on cultured mesangial cells.CONCLUSION.:
‘Peripheral’ CB1R blockade is beneficial in experimental DN and this effect is synergically magnified by CB2R activation.” https://www.ncbi.nlm.nih.gov/pubmed/28387811]]>Cannabinoid type 1 receptor-containing axons innervate NPY/AgRP neurons in the mouse arcuate nucleus.
“Phytocannabinoids, such as THC and endocannabinoids, are well known to promote feeding behavior and to control energy metabolism through cannabinoid type 1 receptors (CB1R). However, the underlying mechanisms are not fully understood.
Generally, cannabinoid-conducted retrograde dis-inhibition of hunger-promoting neurons has been suggested to promote food intake, but so far it has not been demonstrated due to technical limitations.
“Neuropathic pain is a class of pain caused by an injury or diseases of the somatosensory system and characterized by spontaneous pain, allodynia, and hyperalgesia. It is well established that central sensitization is one of the key mechanisms underlying the development and maintenance of neuropathic pain. Cannabinoid receptor 1 (CB1R) of endocannabinoid system modulates synaptic transmission, regulates synaptic plasticity, inhibits central sensitization, and thus attenuates neuropathic pain. Recent studies have shown that activation of CB1R also involves in the relief of neuropathic pain-induced depression.” 
“Treatment of inflammatory pain with opioids is accompanied by unpleasant and, at times, life-threatening side effects.
Cannabis produces antinociception as well as psychotropic effects. It was hypothesized that peripheral cannabinoid receptors outside the central nervous system could be selectively activated for relief of pain.
This study was undertaken to measure the antinociceptive effect of type 1 cannabinoid receptor (CB1r) agonist arachidonylcyclopropylamide (ACPA) in a rat model of inflammatory pain after intrawound administration and the effects were compared with lignocaine.
Lignocaine attenuated evoked pain behaviour whereas ACPA decreased guarding score. This difference was likely due to blockade of sodium ion channels and the activation of peripheral CB1r, respectively. Central side effects were absent after ACPA treatment. Further studies need to be done to assess the effect of ACPA treatment in clinical conditions.”