Search Results (734)

Benign prostatic hyperplasia (BPH) and prostatitis are multifactorial urological disorders associated with chronic inflammation, oxidative stress, and androgenic imbalance. Dysphania ambrosioides (L.) Mosyakin & Clemants contains flavonoids and phenolic acids with well-recognised antioxidant and anti-inflammatory properties; however, its potential activity against the molecular targets of these prostatic disorders has not been systematically evaluated. A comparative quantitative analysis was performed using studies published between 2005 and 2025 that reported antioxidant activity (DPPH assay, IC₅₀ in µg/mL) of D. ambrosioides extracts. Metabolites from extracts with IC₅₀ values below the global mean (398.410 ± 81.810 µg/mL; n = 35) were selected for in silico prioritisation using OSIRIS, PASS, and ProTox 3.0, followed by molecular docking (CB-Dock2) against AR, 5AR2, COX-2, NLRP3, and α1A receptors. Luteolin and rosmarinic acid showed favourable binding energies (−9.5 to −7.7 kcal/mol) comparable in magnitude to reference drugs (finasteride −13.4, celecoxib −11.4, tamsulosin −7.3 kcal/mol). These metabolites, exhibited affinity for androgenic, inflammatory, and adrenergic targets, suggesting their potential to modulate key mechanisms underlying both BPH and prostatitis. This study integrates, for the first time, a quantitative assessment of antioxidant activity with a multitarget in silico analysis of D. ambrosioides, prioritising luteolin and rosmarinic acid as natural candidates with potential antioxidant, anti-inflammatory, and antiandrogenic properties relevant to prostatic health. Full article

Background: Vasopressin (AVP) and its V1a receptor (V1aR) are involved in the regulation of the cardiovascular system. Limited evidence suggests that AVP may also contribute to respiratory regulation. Arterial chemoreflex is the main reflex involved in cardiorespiratory regulation and is triggered from the carotid bodies (CBs), specialized organs that detect changes in arterial blood content. Both increased activity of the vasopressinergic system and enhanced arterial chemoreflex have been found in hypertension. Here, we aimed at determining cardiorespiratory responses to AVP in normo- and hypertensive rats and the involvement of CBs and V1aRs. Methods: Experiments were performed in urethane-anesthetized adult male spontaneously hypertensive (SHR) and normotensive Wistar Kyoto (WKY) rats. Arterial blood pressure (MABP), heart rate (HR), femoral artery blood flow (FABF), minute ventilation (MV), respiratory rate (RR), and end-tidal carbon dioxide (ETCO2) were recorded. We evaluated cardiorespiratory responses to arterial chemoreflex activation with potassium cyanide, intravenous AVP, V1aR antagonist, and CB denervation. Results: In comparison to normotensive animals, SHR rats had significantly greater resting MABP, HR, MV, and enhanced pressor and ventilatory components of arterial chemoreflex. CB denervation caused insignificant changes in cardiorespiratory parameters. Intravenous administration of AVP resulted in a significant increase in MABP in both groups, which was greater in SHR rats, and in ventilatory inhibition, which was present only in SHR rats. CB denervation reduced the pressor response to AVP in normotensive rats and abolished the inhibitory effect of AVP on ventilation in SHR rats. Intravenous administration of the V1aR antagonist caused a significantly greater decrease in MABP in the hypertensive group. Only SHR rats responded with an increase in ventilation after the V1aR antagonist. Effects of AVP were abolished after blockade of V1aRs in both groups. Conclusions: Our study indicates that (i) SHR rats show augmented cardiorespiratory response to AVP, (ii) cardiorespiratory effects of AVP depend on V1aRs; and (iii) respiratory effects of AVP in the hypertensive rats appear to be primarily mediated by CBs. Full article

Cannabinoids, compounds that interact with the endocannabinoid system, have shown promising neuroprotective effects in various neurodegenerative diseases, including those affecting the retina. This review evaluates evidence for the presence and action of cannabinoids in the retina, their function in protecting against oxidative stress and modulating neuroinflammation, and the outcomes observed in animal models of retinal diseases such as glaucoma and age-related macular degeneration (AMD), the most common causes of vision loss. Cannabinoids have proven effective in reducing the neurodegeneration seen in these eye diseases, acting via the CB1 and CB2 cannabinoid receptors. The cannabinoid neuroprotective effect is often of a similar magnitude to the other proven therapy of medical dosage of vitamins, though it confers a greater risk due to neurotoxicity with high THC:CBD ratios, making the vitamin therapy of greater efficacy when time is available. Given the increased ratio of THC:CBD in commercial cannabis strains, rising from 10:1 at the beginning of this century to 100:1 now, the risk of neurotoxicity has increased, reducing the neuroprotective benefit. The proven safety and efficacy of vitamin therapy may be a more viable neuroprotective method than cannabinoid use for chronic conditions, with cannabinoids proving their utility in more acute conditions. This review evaluates both the method of action of cannabinoids and the receptor pathway utilized and compares the suggested therapeutic applicability of cannabinoids with proven vitamin therapy. Full article

Although antiviral therapy has improved quality of life, around 50% of people with HIV (PWH) experience neurodegeneration and cognitive decline. This is prompted in part by the migration of HIV-infected monocyte-derived macrophages (MDMs) to the brain, leading to neuronal death. Previous studies in our lab have shown that HIV-infected MDMs secrete cathepsin B (CATB), which is a pro-inflammatory neurotoxic enzyme that is reduced by the addition of cannabinoid receptor-2 (CB2R) agonist JWH-133 to cell cultures. In this study, we aimed to identify the proteins secreted (secretome) by HIV-infected macrophages exposed to JWH-133 and quantify them using tandem mass tag (TMT) mass spectrometry. Frozen 13-day MDM supernatants from (1) an MDM negative control; (2) HIV+MDM, and (3) HIV+MDM-JWH-133 were compared in triplicate by mass spectrometry (LC/MS/MS) and analyzed for protein identification. Subsequently, the same samples were labeled by TMT labeling and quantified by LC/MS/MS. After a database search, 528 proteins were identified from all groups. Thereafter, proteins with more than three unique peptides and more than 10% coverage were selected for protein identification. Venn diagrams revealed one unique protein secreted by MDM-HIV, 10 unique proteins in HIV+MDM-JWH-133, and 15 common proteins in the three groups. CATB was unique to HIV+MDM. HIV+MDM exposed to JWH-133 showed proteins related to metabolism, cell organization, antiviral activity, and stress response. TMT analysis revealed 1454 proteins with abundance for statistical analysis based on FC ≥ |1.5| and p-value ≤ 0.05, of which Ruvb-like 1 and Hornerin decreased significantly with JWH-133 treatment. Both proteins stimulate HIV replication. In addition, HIV infection upregulated proteins associated with pathways of viral latency that were inhibited by JWH-133. In conclusion, JWH-133 treatment in HIV-infected macrophages leads to the secretion of antiviral host factors and decreases the secretion of proviral, inflammatory, and neurotoxic host factors. Full article

Background: The interaction between the endocannabinoid system (ECS), specifically the CB1 and CB2 cannabinoid receptors, and neuropathy has aroused great research interest due to the possible implications for treatment. Complications following type 1 diabetes, due to impaired glucose metabolism and chronic inflammation, may benefit from targeted therapeutic strategies involving the ECS. This study explores the effects of photobiomodulation therapy (PBMT) on streptozotocin (STZ)-induced diabetic peripheral neuropathy (DPN) in rats. The study assessed body mass, hyperglycemia, mechanical hyperalgesia, and the influence of PBMT on these conditions over four weeks. Results showed that while PBMT did not alter the metabolic aspects of type I diabetes, it significantly reduced mechanical hyperalgesia compared to untreated diabetic neuropathic rats. Notably, cannabinoid receptor antagonists for CB1 and CB2 elicited a transient reversal of this antihyperalgesic effect, indicating a potential role of these receptors in PBMT’s mechanism. However, CB2 modulation was not statistically significant, whereas changes in CB1 receptor expression were observed in the dorsal root ganglia, suggesting its involvement in PBMT’s effects. These findings highlight the importance of CB1 and CB2 receptors in DPN and suggest that PBMT may offer a therapeutic benefit by mitigating mechanical hyperalgesia. Further investigation into cannabinoid receptor dynamics in diabetes could help in new therapeutic strategies for managing diabetic complications. Full article

Background/Objectives: Cannabis is the most widely used illicit substance worldwide, particularly among young adults, with growing acceptance following medical and recreational legalization. Although generally perceived as a drug with low acute toxicity, an expanding body of evidence indicates that cannabinoids can exert relevant cardiovascular effects, including arrhythmias, myocardial ischemia, and sudden cardiac death (SCD). These mechanisms are mediated through complex, dose-dependent interactions among CB1 and CB2 receptors, autonomic imbalance, and endothelial dysfunction. Nevertheless, cannabis-related fatalities remain underestimated in both clinical and forensic settings. Case presentation: Three cases of sudden unexpected death in previously healthy men aged 28, 37, and 37 years are described. All were found deceased at home under non-suspicious circumstances. Forensic autopsies ruled out trauma, coronary atherosclerosis, congenital malformations, or cardiomyopathy. Histological analyses consistently revealed polymorphic myocardial alterations, including interstitial edema, fiber disruption, and focal myocytolysis, without inflammatory infiltrates or necrosis. Toxicological examinations demonstrated the presence of Δ9-tetrahydrocannabinol (THC) and metabolites in peripheral blood and urine, while alcohol and other illicit drugs tested negative. In each case, the cause of death was attributed to arrhythmic sudden cardiac death in temporal association with cannabis use. Conclusions: This case series, integrated with a narrative review of current literature, supports the hypothesis that cannabis consumption can contribute to fatal arrhythmias even in young adults without conventional cardiovascular risk factors. The convergence of autopsy, histopathological, and toxicological findings suggests a potential causal link between THC exposure and sudden unexpected death. These results highlight the importance of systematic postmortem investigations in suspected drug-related fatalities and underscore the need for greater awareness among clinicians, forensic pathologists, and policymakers regarding the underestimated cardiovascular toxicity of cannabis. Full article

Sepsis is a life-threatening syndrome marked by a dysregulated host response to infection, resulting in systemic inflammation, organ dysfunction, and high mortality globally. Despite advancements in supportive care, effective immunomodulatory therapies remain elusive, necessitating exploration of novel biological pathways and subsequent therapeutic development. The endocannabinoid system (ECS), which regulates immune function and homeostasis, has emerged as a key modulator of immunological and metabolic pathways central to sepsis pathophysiology. The ECS mediates its effects through endogenous ligands, G-protein-coupled cannabinoid receptors (CB1 and CB1), and regulatory enzymes that control its synthesis and degradation. Following PRISMA-ScR guidelines, this scoping review synthesizes current evidence on the mechanistic roles of ECS components in experimental and clinical models of sepsis, identifies knowledge gaps, and delineates future areas of work. A comprehensive literature search across multiple databases without restrictions on date or publication type was executed to ensure broad coverage of original studies investigating ECS mechanisms and their intersection with sepsis and septic shock. Across 53 studies, CB2 receptor activation was consistently associated with anti-inflammatory process, organ-protective outcomes, and increased survival rates against septic challenges in preclinical rodent models. CB1 receptor activation trends, however, showed context dependent outcomes. Central antagonism improved hemodynamics and survival rate, but peripheral effects varied with cell type and timing. Non-canonical ECS components (TRPV1, GPR55, PPAR-α, FAAH, MAGL) also contributed to neuroimmune and metabolic regulation. Limited clinical data linked ECS lipid profiles and gene expression with sepsis severity and outcomes. Collectively, ECS modulation, particularly CB2 agonism, TRPV1 activation, and FAAH/MAGL inhibition, shows promise in mitigating sepsis-induced inflammation and organ dysfunction. However, complex, context-dependent effects, especially involving CB1, highlight the need for precision-targeted therapeutic approaches. Further preclinical research is needed to expand generalizable trends to allow translational research to refine ECS-based interventions for sepsis management. Full article

Background: Chronic inflammatory skin disorders, including atopic dermatitis, psoriasis, acne, and chronic wounds, affect nearly two billion people worldwide, impose substantial morbidity and economic burden, and remain only partially controlled by existing therapies. The cutaneous endocannabinoid system (ECS), comprising cannabinoid receptors, endocannabinoids, and their metabolic enzymes, regulates inflammation, pruritus, barrier integrity, and tissue repair; cannabinoid receptor type 2 (CB₂) has emerged as a particularly relevant target. β-Caryophyllene (BCP), a dietary sesquiterpene and highly selective CB₂ agonist with favorable safety and pharmacokinetic attributes, has attracted attention as a promising topical candidate. Methods: We systematically searched PubMed, Embase, and Web of Science (inception–30 July 2025) for studies on “β-caryophyllene” and dermatological outcomes, prioritizing purified BCP and analytically characterized BCP-rich fractions. Quantitative parameters, including tested concentration ranges (0.5 µM–10%) and principal mechanistic outcomes, were extracted to provide a translational context. Results: BCP penetrates the stratum corneum, suppresses NF-κB/MAPK and IL-4/TSLP pathways, enhances Nrf2-driven antioxidant defenses, and accelerates re-epithelialization and collagen remodeling. Across in vitro, in vivo, and formulation studies, BCP produced consistent anti-inflammatory and barrier-restorative effects within this concentration range. CB₂ antagonism attenuated these responses, confirming receptor specificity. BCP’s volatility and autoxidation to β-caryophyllene oxide (BCPO) necessitate stability-by-design strategies using antioxidants, low-oxygen processing, and protective packaging. Human evidence, limited to BCP-rich botanicals such as Copaifera oleoresins, suggests benefits for scars, wounds, and acne but lacks compound-specific validation. Conclusions: BCP exhibits coherent CB₂-mediated anti-inflammatory, antipruritic, antioxidant, and reparative actions with a favorable safety profile. Dose-defined, oxidation-controlled clinical trials of purified BCP are warranted to establish its potential as a steroid-sparing topical therapy. Full article

Background/Objectives: The cannabinoid type 2 receptor (CB₂ receptor) has been extensively studied in recent years due to the benefits associated with its modulation, including the regulation of the inflammatory response, neuroimmunomodulatory properties, and antitumor effects, all with the advantage of lacking significant psychoactive effects. Herein, we report the design, synthesis, characterization, biological assays, and molecular modelling analyses of novel (5/6-chloro-2-aryl-1H-benzo [d]imidazol-1-yl)(4-methoxyphenyl)methanone and 5/6-chloro-1-(4-methoxybenzyl)-2-aryl-1H-benzo [d]imidazole regioisomers as potential cannabinoid type 2 receptor ligands. Methods: The compounds were evaluated for their presumed CB₂ agonist activity using an indirect receptor-dependent apoptotic cell death assay exerted by cannabinoids, using the cell lines HEK293 (low CB₁/CB₂ expression), U-87 MG (high CB₁ expression), and HL-60 (exclusive CB₂ expression), and including the known cannabinoid ligands WIN-55,212-2 and AM630 as reference ligands. Flow cytometry was performed to assess apoptosis. Molecular docking and molecular dynamics simulations were used to explore ligand-receptor interactions at the CB₂ active site. Results: Compounds 3a, 3b’, 3c, and 4b selectively reduced HL-60 cell viability, similar to WIN-55,212-2, while showing no toxicity toward HEK293 or U-87 MG cells. Flow cytometry indicated that compounds 3a and 3c induced apoptosis in HL-60 cells comparable to WIN-55,212-2. Computational studies suggested that both compounds bind within the CB₂ receptor active site predominantly through π–π and hydrophobic interactions involving their benzo [d]imidazole cores, 2-aryl moieties, and 4-methoxybenzoyl scaffolds, resembling the binding patterns of established CB₂ ligands. Conclusions: Compounds 3a and 3c exert selective cytotoxicity against HL-60 cells, likely via a CB₂ agonist-mediated apoptotic mechanism. The applied combined experimental and computational approach provides a rapid, informative strategy for preliminary evaluation of CB₂ ligands and guides subsequent detailed pharmacological studies. Full article

Gliomas are central nervous system primary tumors that are distinguished by heterogeneity, broad-based infiltration, and metabolic reprogramming that sustains proliferation, invasion, and therapy refractoriness. Oxidative stress—a state of imbalance between the production of reactive oxygen species (ROS) and the antioxidant defense—and disturbed iron metabolism are central drivers of glioma biology. The aim of this study was to evaluate ROS production, sulfane sulfur levels, the expression of proteins with antioxidant properties, such as L-cysteine-metabolizing enzymes (cystathionine β-synthase, CBS; cysteine dioxygenase 1, CDO1; cystathionine γ-lyase, CTH; 3-mercaptopyruvate sulfurtransferase, MPST; thiosulfate sulfurtransferase, TST) and non-enzymatic proteins (p53; transferrin receptor 1, TfR1), in human brain cancer cells differing in malignancy: 1321N1 astrocytoma and T98G glioblastoma. Western blotting analysis demonstrated that the expression of CBS, CDO1, and TfR1 was significantly increased in T98G cells, while CTH, MPST, TST, and p53 were comparably expressed in both cell lines. Quantitative assays revealed that T98G cells harbored significantly higher sulfane sulfur levels and higher numbers of ROS-positive cells compared to 1321N1 cells. Our results suggest that glioblastoma but not astrocytoma cells adapt sulfur and iron metabolism to provide proliferation capacity against chronic oxidative stress. It seems that CBS as well as CDO1 may significantly increase the antioxidant potential of T98G cells. In summary, this study suggests a differing metabolic vulnerability identifiable only in high-grade glioma cells and provides a potential novel molecular target for therapy. Full article

Background/Objectives: Dysgeusia is a taste disorder commonly associated with chronic inflammation, reducing the quality of life, particularly in ageing populations or individuals with non-communicable chronic diseases. This study aimed to evaluate the effect of β-Caryophyllene, a natural sesquiterpene and agonist of the cannabinoid receptor 2 (CB2), on dysgeusia through an analysis of inflammation, Renin–Angiotensin System (RAS) and taste perception. Methods: Male BALB/c mice were subjected to a dysgeusia model induced by molecular mimicry with lipopolysaccharide. Animals received intraperitoneal injections of lipopolysaccharide in a chronic–persistent regimen, starting at a dose of 35 μg/100 g body weight for 7 days until reaching a final concentration of 250 μg/100 g and a daily oral administration of β-Caryophyllene at a dose of 10 mg/kg. The effect of β-Caryophyllene on taste perception, inflammatory biomarkers, RAS key-elements, CB2 expression and physiological parameters was evaluated. Results: Data indicate that β-Caryophyllene attenuates systemic inflammation by decreasing IL-1β and IL-6 and increasing ACE2 enzymatic activity in lingual tissue. Also, it was shown that the sesquiterpene reduced taste cell apoptosis and improved sucrose preference, suggesting a feasible restoration of taste dysfunction. Conclusions: These findings demonstrate that β-Caryophyllene could be a potential candidate for treating dysgeusia due to its putative anti-inflammatory and angiotensinergic effects. Full article

CB₁ agonist compounds may be potential drug candidates for the treatment of gliomas, as they have been shown to inhibit tumor cell proliferation, induce apoptosis, and reduce angiogenesis in various preclinical models. Their ability to modulate the endocannabinoid system suggests a promising therapeutic approach for targeting glioma growth and progression. Herein, we report the design, synthesis, biological studies, and bioinformatics assays of novel benzo[d]imidazole–naphthalen-arylmethanone regioisomers with affinity for the CB₁ receptor, as well as propose an indirect methodology to evaluate their presumed CB₁ agonist activity. Compounds that showed a propensity for binding to the CB₁ receptor were regioisomers 4d, 5b, 5e, 5f, and 5f′. Likewise, derivatives that displaced more than 50% of the radioligand [³H]CP-55940 at the CB₁ receptor were subjected to in vitro viability experiments. Compounds 4d, 5b, 5e, and 5f′ showed toxicity against U87MG cells (malignant glioma) in a considerable percentage. Notably, compound 5f′ showed CB₁ affinity, with a K_i of 2.12 µM, and was selectively toxic to U87MG cells, which highly express the CB₁ receptor, while exhibiting no toxicity toward the healthy HEK293 cell line, which expresses both cannabinoid receptors at negligible levels. Docking studies at the CB₁ orthosteric site indicate that 5f′ forms π-π interactions, a T-shaped interaction, and hydrogen bonding through the oxygen atom of the furan ring. Biologically, our experimental indirect model-based on a simple viability assay is supported by well-established evidence that activation of CB₁ and CB₂ receptors by agonists induces cell death and inhibits tumor cell growth. Structurally, we conclude that the presence of a furan ring at the 2-position of the benzo[d]imidazole core is beneficial for the development of new ligands with potential CB₁ agonist activity. Full article

17β-estradiol (E2) enhances the cerebellar molecular layer interneurons (MLIs)—Purkinje cells (PCs) synaptic transmission via activation of the Erβ in vivo in mice. Whether E2 regulates cerebellar MLI-PC synaptic plasticity is unknown. To investigate the mechanism of E2, we evaluated the modulation of facial stimulation-evoked MLI-PC long-term plasticity in mice. Cell-attached recordings from PCs of Crus II were performed using an Axopatch-700B patch-clamp amplifier. The MLI-PC synaptic transmission was evoked by facial stimulation. Immunohistochemistry was used to detect the expression of ERβ. Under control conditions, 1 Hz facial stimuli induced long-term depression (LTD) at MLI-PC synapses, characterized by a sustained reduction in P1 amplitude and a simple spike (SS) pause. The facial stimulus-induced MLI-PC LTD was completely prevented by E2, but this effect was reversed by a selective ERα/ERβ antagonist, ICI182780. Blockade of cannabinoid receptor 1 (CB1R) eliminated the MLI-PC LTD under control conditions, but revealed an E2-triggered long-term potentiation (LTP). The E2-triggered MLI-PC LTP persisted in the presence of an ERα antagonist but was absent in the presence of an ERβ antagonist PHTPP. The E2-triggered MLI-PC LTP remained unaffected by protein kinase A inhibition but was abolished by inhibition of protein kinase C (PKC) and intracellular Ca²⁺ depletion. Moreover, ERβ immunoreactivity was abundantly distributed around dendrites and somas of PCs in the Crus II region of the mouse cerebellar cortex. The present results suggest that E2 activates ERβ, thereby triggering facial stimulation-induced MLI-PC LTP via the PKC signaling cascade, which occludes CB1R-dependent MLI-PC LTD in the cerebellar cortex of mice in vivo. Full article

Previous research has demonstrated that the transient bilateral common carotid artery occlusion and reperfusion (BCCAO/R) effectively models early brain inflammation resulting from sudden hypoperfusion and subsequent reperfusion. According to studies showing that diet and nutrition strongly influence brain neuroplasticity, in this study we evaluated whether kaempferol (KAM), a dietary flavonoid, offers neuroprotection in a rat BCCAO/R model. Adult Wistar rats were gavage fed a single dose of KAM (40 mg) six hours before surgery. Comprehensive lipidomic and molecular analyses were conducted on samples from the frontal and temporal-occipital cortices, as well as the plasma. In the frontal cortex, KAM elevated anti-inflammatory N-acylethanolamines palmitoylethanolamide (PEA), oleoylethanolamide (OEA), and docosahexaenoylethanolamide (DHAEA) and reduced oxidized arachidonic acid metabolites. KAM also downregulated cyclooxygenase- 2 (COX-2) protein and selectively decreased the endocannabinoid 2-arachidonoylglycerol (2-AG), showing a shift in AA metabolism. These molecular changes correlated with increased levels of peroxisome proliferator-activated receptor alpha (PPARα) and cannabinoid receptors CB1R and CB2R, supporting activation of both nuclear and membrane-bound anti-inflammatory pathways. No significant changes were observed in the temporal-occipital cortex. In plasma, DHAEA levels increased similarly to those in the cortex. However, rises in PEA and OEA were detected only in sham-operated KAM-treated animals, suggesting possible central redistribution under hypoperfusion/reperfusion stress. In summary, these findings demonstrate that KAM exerts dual anti-inflammatory effects by inhibiting COX-2-mediated prostanoid synthesis and promoting PPARα-driven lipid signaling. This dual mechanism highlights the potential of KAM as a dietary intervention to reduce neuroinflammation associated with hypoperfusion–reperfusion challenges. Full article

Intracellular emetic signals involved in the cannabinoid CB₁ receptor inverse agonist/antagonist SR141716A were investigated. SR141716A (20 mg/kg, i.p.)-evoked vomiting occurred via both the central and peripheral mechanisms. This was accompanied by robust emesis-associated increases in the following: (i) c-fos- and phospho-glycogen synthase kinase-3α/β (p-GSK-3αβ)-expression in the shrew’s dorsal vagal complex (DVC), (ii) phospho-extracellular signal-regulated kinase1/2 (p-ERK_1/2) expression in both the DVC and jejunal enteric nervous system, and (iii) time-dependent upregulation of cAMP levels and phosphorylation of protein kinase A (PKA), protein kinase B (Akt), GSK-3α/β, ERK_1/2, and protein kinase C αβII (PKCαβII) in the brainstem. SR141716A-evoked emetic parameters were attenuated by diverse inhibitors of the following: PKA, ERK_1/2, GSK-3, phosphatidylinositol 3-kinase (PI3K)-Akt pathway, phospholipase C (PLC), PKC, Ca²⁺/calmodulin-dependent protein kinase II (CaMKII), L-type Ca²⁺ channel (LTCC), store-operated Ca²⁺ entry (SOCE), inositol trisphosphate receptor (IP3R), ryanodine receptor (RyRs), both 5-HT₃-, and D_2/3-receptor antagonists, and the transient receptor potential vanilloid 1 receptor (TRPV1R) agonist. SR141716A appears to evoke vomiting via inverse agonist activity involving emesis-associated kinases, including cAMP/PKA, ERK_1/2, PI3K/Akt/GSK-3, PLC/PKCαβII, and CaMKII, which depend upon Ca²⁺ mobilization linking extracellular Ca²⁺ entry via plasma membrane Ca²⁺ channels (LTCC, SOCE, TRIPV1R) and intracellular Ca²⁺ release via IP3Rs and RyRs. The 5-HT₃, NK₁, and D_2/3 receptors also contribute to SR141716A-mediated vomiting. Full article