Saliva serves multiple important functions within the body that we typically take for granted, such as helping prepare food for swallowing and defense against oral pathogens. Dry mouth is a primary symptom of Sjӧgren's syndrome and is a side effect of many drug treatments. Cannabis users frequently report dry mouth, but the basis for this is still unknown. If the effects occur via the endogenous cannabinoid signaling system, then this may represent a novel mechanism for the regulation of salivation. We examined expression of cannabinoid CB1 receptors in submandibular salivary gland using immunohistochemistry and tested regulation of salivation by THC and cannabinoid-related ligands. We now report that CB1 receptors are expressed in the axons of cholinergic neurons innervating the submandibular gland. No staining is seen in submandibular gland epithelial cells (acinar and ductal), or myoepithelial cells (MECs). Treatment with THC (4 mg/kg, IP) or the cannabinoid receptor agonist CP55940 (0.5 mg/kg) reduced salivation in both male and female mice 1 h after treatment. CBD had no effect on its own but reversed the effect of THC in a concentration-dependent manner. Neither the CB1 receptor antagonist SR141716 (4 mg/kg) nor the CB2-selective agonist JWH133 (4 mg/kg) had an effect on salivation. We also found that fatty acid amide hydrolase (FAAH), the enzyme that metabolizes the endocannabinoid anandamide and related lipids, regulates salivation. Salivation was reduced in FAAH knockout mice as well as mice treated with the FAAH blocker URB597 (4 mg/kg). URB597 had no effect in CB1 knockout mice. FAAH protein is detected intracellularly in acinar but not ductal epithelial cells. In lipidomics experiments, we found that FAAH knockout mice chiefly had elevated levels of acylethanolamines, including anandamide, and reduced levels of acyglycines. Our results are consistent with a model wherein endocannabinoids activate CB1 receptors on cholinergic axons innervating the submandibular gland. THC likely acts by plugging into this system, activating CB1 receptors to reduce salivation, thus offering a mechanism underlying the dry mouth reported by cannabis users.

Cannabinoid CB2 receptors (CB2Rs) are expressed in mouse brain dopamine (DA) neurons and are involved in several DA-related disorders. However, the cell type-specific mechanisms are unclear since the CB2R gene knockout mice are constitutive gene knockout. Therefore, we generated Cnr2-floxed mice that were crossed with DAT-Cre mice, in which Cre- recombinase expression is under dopamine transporter gene (DAT) promoter control to ablate Cnr2 gene in midbrain DA neurons of DAT-Cnr2 conditional knockout (cKO) mice. Using a novel sensitive RNAscope in situ hybridization, we detected CB2R mRNA expression in VTA DA neurons in wildtype and DAT-Cnr2 cKO heterozygous but not in the homozygous DAT-Cnr2 cKO mice. Here we report that the deletion of CB2Rs in dopamine neurons enhances motor activities, modulates anxiety and depression-like behaviors and reduces the rewarding properties of alcohol. Our data reveals that CB2Rs are involved in the tetrad assay induced by cannabinoids which had been associated with CB1R agonism. GWAS studies indicates that the CNR2 gene is associated with Parkinson's disease and substance use disorders. These results suggest that CB2Rs in dopaminergic neurons may play important roles in the modulation of psychomotor behaviors, anxiety, depression, and pain sensation and in the rewarding effects of alcohol and cocaine.

Taxanes such as paclitaxel, which are chemotherapeutic drugs, cause dose-dependent painful neuropathy in some patients. We investigated whether coadministration of minocycline and indomethacin produces antinociceptive effects in mice with paclitaxel-induced neuropathic thermal hyperalgesia and if the cannabinoid system is involved. Previously, we reported that coadministration of these two drugs results in antinociception against inflammatory pain at doses where either drug alone lack significant activity. In the current study, we observed that treatment of female mice with indomethacin or minocycline alone did not affect established paclitaxel-induced thermal hyperalgesia, whereas coadministration of the two drugs attenuated it. In male mice indomethacin had some antihyperalgesic activity, whilst minocycline did not. Coadministration of the two drugs had supraadditive antihyperalgesic activity in male mice. Administration of a cannabinoid CB1 receptor antagonist AM 251 blocked the antihyperalgesic effects of the combination of minocycline and indomethacin in both male and female mice. In conclusion our results indicate that coadministration of minocycline and indomethacin abrogates established paclitaxel-induced neuropathic thermal hyperalgesia in mice, and the potentiation of the antinociceptive effects of this combination involves the cannabinoid system.

The cannabinoid type 1 (CB1) receptor and the capsaicin receptor (TRPV1) exhibit co-expression and complex, but largely unknown, functional interactions in a sub-population of primary sensory neurons (PSN). We report that PSN co-expressing CB1 receptor and TRPV1 form two distinct sub-populations based on their pharmacological properties, which could be due to the distribution pattern of the two receptors. Pharmacologically, neurons respond either only to capsaicin (COR neurons) or to both capsaicin and the endogenous TRPV1 and CB1 receptor ligand anandamide (ACR neurons). Blocking or deleting the CB1 receptor only reduces both anandamide- and capsaicin-evoked responses in ACR neurons. Deleting the CB1 receptor also reduces the proportion of ACR neurons without any effect on the overall number of capsaicin-responding cells. Regarding the distribution pattern of the two receptors, neurons express CB1 and TRPV1 receptors either isolated in low densities or in close proximity with medium/high densities. We suggest that spatial distribution of the CB1 receptor and TRPV1 contributes to the complexity of their functional interaction.

Capsaicin, the spicy component of hot chili peppers activates the TRPV1 pain receptors, and causes rapid desensitization. Capsaicin also ameliorates cisplatin-induced nephrotoxicity. Cisplatin, a commonly used anti-neoplastic agent for solid tumors causes significant hearing loss, nephrotoxicity and peripheral neuropathy. Upregulation of cochlear TRPV1 expression is related to cisplatin-mediated ototoxicity. Here we report that direct TRPV1 activation by localized trans-tympanic (TT) or oral administration of capsaicin (TRPV1 agonist) prevents cisplatin ototoxicity by sustained increased activation of pro-survival transcription factor signal transducer and activator of transcription (STAT3) in the Wistar rat. Cisplatin treatment produced prolonged activation of pro-apoptotic Ser727 p-STAT1 and suppressed Tyr705-p-STAT3 for up to 72 h in the rat cochlea. Our data indicate that capsaicin causes a transient STAT1 activation via TRPV1 activation, responsible for the previously reported temporary threshold shift. Additionally, we found that capsaicin increased cannabinoid receptor (CB2) in the cochlea, which leads to pro-survival Tyr705-p-STAT3 activation. This tilts the delicate balance of p-STAT3/p-STAT1 towards survival. Furthermore, capsaicin mediated protection is lost when CB2 antagonist AM630 is administered prior to capsaicin treatment. In conclusion, capsaicin otoprotection appears to be mediated by activation of CB2 receptors in the cochlea which are coupled to both STAT1 and STAT3 activation.

The aim of the study was to investigate the influence of intraperitoneal N-arachidonoylethanolamide (AEA) on taste preference for feed and water, tongue taste receptor signalling (TAS1R2, GNAT3), and endocannabinoid (CNR1, CNR2, GPR55) and opioid (OPRD1, OPRK1, OPRM1, OPRL1) receptors in the amygdala and nucleus accumbens in periparturient cows. We conducted taste preference tests using unaltered, umami-tasting, and sweet-tasting water and feed, before and after calving. After calving, eight cows received AEA injections (3 µg/(kg bodyweight × day), 25 days), whereas eight control (CON) cows received saline injections. Tissue was sampled 30 days after calving. Before calving, both cow groups preferred sweet-tasting feed and umami-tasting water. After calving, only the AEA-treated group preferred sweet-tasting feed, whereas the CON group showed no clear taste preference. In the amygdala, the mRNA expression of CNR1, OPRD1 (left hemisphere) and OPRK1 (right hemisphere) was lower in AEA animals than in CON animals, whereas no differences were found in the nucleus accumbens and tongue taste receptor expression. In conclusion, AEA administration enhanced existing taste preferences and reduced the expression of specific endocannabinoid and opioid receptors in the amygdala. The results support endocannabinoid-opioid interactions in the control of taste-dependent feed preference in early lactating cows.

The endocannabinoid system has been postulated to help restrict cancer progression and maintain osteoblastic function during bone metastasis. Herein, the effects of cannabinoid receptor (CB) type 1 and 2 activation on breast cancer cell and osteoblast interaction were investigated by using ACEA and GW405833 as CB1 and CB2 agonists, respectively. Our results showed that breast cancer cell (MDA-MB-231)-derived conditioned media markedly decreased osteoblast-like UMR-106 cell viability. In contrast, media from MDA-MB-231 cells pre-treated with GW405833 improved UMR-106 cell viability. MDA-MB-231 cells were apparently more susceptible to both CB agonists than UMR-106 cells. Thereafter, we sought to answer the question as to how CB agonists reduced MDA-MB-231 cell virulence. Present data showed that co-activation of CB1 and CB2 exerted cytotoxic effects on MDA-MB-231 cells by increasing apoptotic cell death through suppression of the NF-κB signaling pathway in an ROS-independent mechanism. ACEA or GW405833 alone or in combination also inhibited MDA-MB-231 cell migration. Thus, it can be concluded that the endocannabinoid system is able to provide protection during breast cancer bone metastasis by interfering cancer and bone cell interaction as well as by the direct suppression of cancer cell growth and migration.

The first synthetic cannabinoid receptor agonists (SCRAs) were designed as tool compounds to study the endocannabinoid system's two predominant cannabinoid receptors, CB1R and CB2R. Unfortunately, novel SCRAs now represent the most rapidly proliferating novel psychoactive substances (NPS) of abuse globally. Unlike ∆9-tetrahydrocannabinol, the CB1R and CB2R partial agonist and the intoxicating constituent of Cannabis, many SCRAs characterized to date are full agonists of CB1R. Gaining additional insight into the pharmacological activity of these SCRAs is critical to assess and regulate NPSs as they enter the marketplace. The purpose of this study was to assess select SCRAs recently identified by Canadian police, border service agency, private companies and the illicit market as potential CB1R and CB2R agonists. To this end, fifteen SCRAs were screened for in vitro activity and in silico interactions at CB1R and CB2R. Several SCRAs were identified as being highly biased for cAMP inhibition or βarrestin2 recruitment and receptor subtype selectivity between CB1R and CB2R. The indazole ring and halogen-substituted butyl or pentyl moieties were identified as two structural features that may direct βarrestin2 bias. Two highly-biased SCRAs-JWH-018 2'-napthyl-N-(3-methylbutyl) isomer (biased toward cAMP inhibition) and 4-fluoro MDMB-BINACA (biased toward βarrestin2 recruitment) displayed unique and differential in vivo activity in mice. These data provide initial insight into the correlations between structure, signalling bias, and in vivo activity of the SCRAs.

Signaling through integral membrane G protein-coupled receptors (GPCRs) is influenced by lipid composition of cell membranes. By using novel high affinity ligands of human cannabinoid receptor CB2, we demonstrate that cholesterol increases basal activation levels of the receptor and alters the pharmacological categorization of these ligands. Our results revealed that (2-(6-chloro-2-((2,2,3,3-tetramethylcyclopropane-1-carbonyl)imino)benzo[d]thiazol-3(2H)-yl)ethyl acetate ligand (MRI-2646) acts as a partial agonist of CB2 in membranes devoid of cholesterol and as a neutral antagonist or a partial inverse agonist in cholesterol-containing membranes. The differential effects of a specific ligand on activation of CB2 in different types of membranes may have implications for screening of drug candidates in a search of modulators of GPCR activity. MD simulation suggests that cholesterol exerts an allosteric effect on the intracellular regions of the receptor that interact with the G-protein complex thereby altering the recruitment of G protein.

Δ9-tetrahydrocannabinol (Δ9-THC) is known for its antitumor activity and palliative effects. However, its unfavorable physicochemical and biopharmaceutical properties, including low bioavailability, psychotropic side effects and resistance mechanisms associated to dosing make mandatory the development of successful drug delivery systems. In this work, transferring (Tf) surface-modified Δ9-THC-loaded poly(lactide-co-glycolic) nanoparticles (Tf-THC-PLGA NPs) were proposed and evaluated as novel THC-based anticancer therapy. Furthermore, in order to assess the interaction of both the nanocarrier and the loaded drug with cancer cells, a double-fluorescent strategy was applied, including the chemical conjugation of a dye to the nanoparticle polymer along with the encapsulation of either a lipophilic or a hydrophilic dye. Tf-THC PLGA NPs exerted a cell viability decreased down to 17% vs. 88% of plain nanoparticles, while their internalization was significantly slower than plain nanoparticles. Uptake studies in the presence of inhibitors indicated that the nanoparticles were internalized through cholesterol-associated and clathrin-mediated mechanisms. Overall, Tf-modification of PLGA NPs showed to be a highly promising approach for Δ9-THC-based antitumor therapies, potentially maximizing the amount of drug released in a sustained manner at the surface of cells bearing cannabinoid receptors.

Of the three primary cannabinoids in cannabis: Δ9-Tetrahydrocannabinol (Δ9-THC), cannabidiol (CBD) and cannabinol (CBN), very little is known about the actions of CBN, the primary oxidative metabolite of THC. Our goal was to determine if CBN exposure during gastrulation alters embryonic development, and if so, does it act via the canonical cannabinoid receptors. Zebrafish embryos were exposed to CBN during gastrulation and exhibited dose-dependent malformations, increased mortality, decreased locomotion and a reduction in motor neuron branching. Moreover, larva showed a significant reduction in the response to sound stimuli. CBN exposure altered the development of hair cells associated with otic vesicles and the lateral line. Pharmacological block of Cb2rs with AM 630 or JTE 907 prevented many of the CBN-induced developmental defects, while block of Cb1rs with AM 251 or CP 945598 had little or no effect. Altogether we show that embryonic exposure to CBN results in alterations in embryonic growth, neuronal and hair cell development, physiology and behavior via Cb2r-mediated mechanisms.

The insular cortex plays pivotal roles in taste learning. As cellular mechanisms of taste learning, long-term potentiation (LTP) at glutamatergic synapses is well studied. However, little is known about long-term changes of synaptic efficacy at GABAergic synapses in the insular cortex. Here, we examined the synaptic mechanisms of long-term plasticity at GABAergic synapses in layer V pyramidal neurons of the mouse insular cortex. In response to a prolonged high-frequency stimulation (HFS), GABAergic synapses displayed endocannabinod (eCB)-mediated long-term depression (LTDGABA). When cannabinoid 1 receptors (CB1Rs) were blocked by a CB1R antagonist, the same stimuli caused LTP at GABAergic synapses (LTPGABA) which was mediated by production of nitric oxide (NO) via activation of NMDA receptors. Intriguingly, NO signaling was necessary for the induction of LTDGABA. In the presence of leptin which blocks CB1 signaling, the prolonged HFS caused LTPGABA which was mediated by NO signaling. These results indicate that long-term plasticity at GABAergic synapses in the insular cortex can be modulated by combined effects of eCB and NO signaling. These forms of GABAergic synaptic plasticity in the insular cortex may be crucial synaptic mechanisms in taste learning.

Cannabinoids are involved in the regulation of neural stem cell biology and their receptors are expressed in the neurogenic niches of adult rodents. In the spinal cord of rats and mice, neural stem cells can be found in the ependymal region, surrounding the central canal, but there is evidence that this region is largely different in adult humans: lacks a patent canal and presents perivascular pseudorosettes, typically found in low grade ependymomas. Using Laser Capture Microdissection, Taqman gene expression assays and immunohistochemistry, we have studied the expression of endocannabinoid system components (receptors and enzymes) at the human spinal cord ependymal region. We observe that ependymal region is enriched in CB1 cannabinoid receptor, due to high CB1 expression in GFAP+ astrocytic domains. However, in human spinal cord levels that retain central canal patency we found ependymal cells with high CB1 expression, equivalent to the CB1(HIGH) cell subpopulation described in rodents. Our results support the existence of ependymal CB1(HIGH) cells across species, and may encourage further studies on this subpopulation, although only in cases when central canal is patent. In the adult human ependyma, which usually shows central canal absence, CB1 may play a different role by modulating astrocyte functions.

Neuropathic pain typically appears in a region innervated by an injured or diseased nerve and, in some instances, also on the contralateral side. This so-called mirror image pain is often observed in mice lacking CB2 receptors after sciatic nerve injury, but the underlying mechanisms for this phenotype largely remain unclear. Here we focused on peripheral leptin signaling, which modulates neuropathic pain development and interacts with the endocannabinoid system. Leptin production is induced at the site of nerve injury in CB2-deficient mice (CB2-KO) mice and wild type controls (WT). However, induction of leptin receptor expression was only observed in the injured nerve of CB2-KO mice. This was paralleled by a stimulation of the leptin receptor-downstream STAT3 signaling and an infiltration of F4/80-positive macrophages. Interestingly, an upregulation of leptin receptor expression STAT3 activity and macrophage infiltration was also observed on the non-injured nerve of CB2-KO mice thus reflecting the mirror image pain in CB2-KO animals. Importantly, perineurally-administered leptin-neutralizing antibodies reduced mechanical hyperalgesia, blocked mirror image pain and inhibited the recruitment of F4/80-positive macrophages. These results identify peripheral leptin signaling as an important modulator of CB2 signaling in neuropathic pain.

The inhibitory effects demonstrated by activation of cannabinoid receptors (CB) on cancer proliferation and migration may also play critical roles in controlling bladder cancer (BC). CB expression on human normal and BC specimens was tested by immunohistochemistry. Human BC cells RT4 and RT112 were challenged with CB agonists and assessed for proliferation, apoptosis, and motility. Cellular sphingolipids (SL) constitution and metabolism were evaluated after metabolic labelling. CB1-2 were detected in BC specimens, but only CB2 was more expressed in the tumour. Both cell lines expressed similar CB2. Exposure to CB2 agonists inhibited BC growth, down-modulated Akt, induced caspase 3-activation and modified SL metabolism. Baseline SL analysis in cell lines showed differences linked to unique migratory behaviours and cytoskeletal re-arrangements. CB2 activation changed the SL composition of more aggressive RT112 cells by reducing (p < 0.01) Gb3 ganglioside (-50 ± 3%) and sphingosine 1-phosphate (S1P, -40 ± 4%), which ended up to reduction in cell motility (-46 ± 5%) with inhibition of p-SRC. CB2-selective antagonists, gene silencing and an inhibitor of SL biosynthesis partially prevented CB2 agonist-induced effects on cell viability and motility. CB2 activation led to ceramide-mediated BC cell apoptosis independently of SL constitutive composition, which instead was modulated by CB2 agonists to reduce cell motility.

Cannabinoid receptor 2 (CB2) signaling modulates microglial responses to inflammatory stimuli. Our previous studies demonstrated that genetic deletion of CB2 inhibits microglial activation during inflammatory stimulation of toll-like receptors (TLRs) or in neurodegenerative conditions. However, we cannot exclude developmental effects of the constitutive CB2 knockout (CB2-/-), which could mediate compensatory outcomes in CB2-/- mice. In the present study, we therefore tested whether acute pharmacological inhibition of CB2 receptor has a similar effect on microglial activation as in CB2-/- in response to inflammatory stimulation. Our findings suggest that the CB2-specific antagonist SR144528 has little or no effect on LPS/IFN-γ-induced activation in primary microglia or organotypic hippocampal slice cultures at nanomolar concentrations. We show that SR144528 did not alter LPS/IFN-γ-mediated microglial cytokine secretion, Iba1 and CD68 staining intensity or morphology at 1 and 10 nM. Although SR144528 suppressed LPS/IFN-γ-induced microglial activation at 1 µM, this anti-inflammatory effect was not dependent on CB2 receptors and exceeded the Ki on CB2 receptors by more than a thousand-fold. Thus, SR144528 does not mimic the anti-inflammatory effects observed in the CB2-/- microglia after LPS/IFN-γ stimulation. Therefore, we propose that the deletion of CB2 probably triggered an adaptive mechanism, making microglia less responsive to inflammatory stimulation.

Activation of CB2 has been demonstrated to induce directed immune cell migration. However, the ability of CB2 to act as a chemoattractant receptor in macrophages remains largely unexplored. Using a real-time chemotaxis assay and a panel of chemically diverse and widely used CB2 agonists, we set out to examine whether CB2 modulates primary murine macrophage chemotaxis. We report that of 12 agonists tested, only JWH133, HU308, L-759,656 and L-759,633 acted as macrophage chemoattractants. Surprisingly, neither pharmacological inhibition nor genetic ablation of CB2 had any effect on CB2 agonist-induced macrophage chemotaxis. As chemotaxis was pertussis toxin sensitive in both WT and CB2(-/-) macrophages, we concluded that a non-CB1/CB2, Gi/o-coupled GPCR must be responsible for CB2 agonist-induced macrophage migration. The obvious candidate receptors GPR18 and GPR55 could not mediate JWH133 or HU308-induced cytoskeletal rearrangement or JWH133-induced β-arrestin recruitment in cells transfected with either receptor, demonstrating that neither are the unidentified GPCR. Taken together our results conclusively demonstrate that CB2 is not a chemoattractant receptor for murine macrophages. Furthermore we show for the first time that JWH133, HU308, L-759,656 and L-759,633 have off-target effects of functional consequence in primary cells and we believe that our findings have wide ranging implications for the entire cannabinoid field.

We investigated whether glutamate receptor subunit 2 (GluR2) is involved in EA pretreatment-induced neuroprotection via cannabinoid CB1 receptors (CB1R) after global cerebral ischemia in mice. Two hours after electric acupuncture (EA) pretreatment, global cerebral ischemia (GCI) was induced by bilateral common carotid artery occlusion (BCCAO) for 20 min. The GluR2 expression was examined in the hippocampus after reperfusion. Cell survival, neuronal apoptosis, the Bax/Bcl-2 ratio and neurological scores were evaluated at 24 h after BCCAO in the presence or absence of the GluR2 inhibitor. Furthermore, the GluR2 was determined in the presence and absence of CB1R inhibitor. Our results showed EA pretreatment enhanced expression of GluR2 in the hippocampus 2 h after reperfusion. Moreover, EA pretreatment improved neurological outcome, promoted cell survival, inhibited neuronal apoptosis, and decreased the Bax/Bcl-2 ratio after reperfusion. GluR2 knockdown by GluR2 siRNA effectively reversed the beneficial effects of EA pretreatment. Furthermore, CB1R siRNA and two CB1R antagonists blocked the elevation of GluR2 expression by EA pretreatment, whereas the two CB1R agonists up-regulated GluR2 expression as EA pretreatment. In conclusion, GluR2 up-regulation is involved in neuroprotection of EA pretreatment against GCI through CB1R, suggesting that GluR2 may be a novel target for stroke intervention.

LH-21 is a triazol derivative that has been described as a low-permeant neutral CB1 antagonist, though its pharmacology is still unclear. It has been associated with anti-obesity actions in obese rats. However, its role in preventing type 2 diabetes (T2D) onset have not been studied yet. Given CB1 receptors remain as potential pharmacological targets to fight against obesity and T2D, we wanted to explore the metabolic impact of this compound in an animal model of obesity and pre-diabetes as well as the lack of relevant actions in related central processes such as anxiety. C57BL/6J mice were rendered obese and pre-diabetic by feeding a high-fat diet for 15 weeks and then treated with LH-21 or vehicle for two weeks. Food intake, body weight and glucose handling were assessed, together with other relevant parameters. Behavioural performance was evaluated by the open field test and the elevated plus maze. LH-21 did not affect food intake nor body weight but it improved glucose handling, displaying tissue-specific beneficial actions. Unexpectedly, LH-21 induced anxiolysis and reverted obesity-induced anxiety, apparently through GPR55 receptor. These results suggest that LH-21 can be a new candidate to fight against diabetes onset. Indeed, this compound shows potential in counteracting obesity-related anxiety.

Aged skeletal muscle undergoes metabolic and structural alterations eventually resulting in a loss of muscle strength and mass, i.e. age-related sarcopenia. Therefore, novel targets for muscle growth purposes in elderly are needed. Here, we explored the role of the cannabinoid system in muscle plasticity through the expression of muscle cannabinoid receptors (CBs) in young and old humans. The CB1 expression was higher (+ 25%; p = 0.04) in muscle of old (≥ 65 years) vs. young adults (20-27 years), whereas CB2 was not differently expressed. Furthermore, resistance exercise tended to increase the CB1 (+ 11%; p = 0.055) and CB2 (+ 37%; p = 0.066) expression in muscle of older adults. Interestingly, increases in the expression of CB2 following resistance exercise positively correlated with changes in key mechanisms of muscle homeostasis, such as catabolism (FOXO3a) and regenerative capacity (Pax7, MyoD). This study for the first time shows that CB1 is differentially expressed with aging and that changes in CB2 expression upon resistance exercise training correlate with changes in mediators that play a central role in muscle plasticity. These data confirm earlier work in cells and mice showing that the cannabinoid system might orchestrate muscle growth, which is an incentive to further explore CB-based strategies that might counteract sarcopenia.