Potentiation of morphine-induced antinociception by harmaline: involvement of μ-opioid and ventral tegmental area NMDA receptors

Alijanpour, Sakineh; Zarrindast, Mohammad‐Reza

doi:10.1007/s00213-019-05389-8

Cited by 8 publications

(5 citation statements)

References 72 publications

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“…Harmaline is a naturally occurring β‐carboline alkaloid that is isolated from the seeds of Peganum harmala (Wang, Wang, Jiang, Zeng, & He, 2015). Previous studies have reported that harmaline exhibits numerous clinical effects, including antiinflammatory, antipruritic, and antitumor properties (Alijanpour & Zarrindast, 2020; Iranshahy et al, 2019; Nasehi, Meskarian, Khakpai, & Zarrindast, 2016; Xu et al, 2018). Although harmaline has shown antitumor effects in gastric and liver cancer (Wang et al, 2015; Xu et al, 2018), the anticancer activity of harmaline and its molecular mechanism have not been characterized in ESCC.…”

Section: Introductionmentioning

confidence: 99%

Harmaline isolated from Peganum harmala suppresses growth of esophageal squamous cell carcinoma through targeting mTOR

Zhang

Shi

Xie

et al. 2021

Phytotherapy Research

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Harmaline is a naturally occurring β-carboline alkaloid that is isolated from Peganum harmala. It has shown efficacy in treating Parkinson's disease and has been reported to exhibit antimicrobial and anticancer properties. However, the molecular mechanism of harmaline in the context of esophageal squamous cell carcinoma (ESCC) has not been characterized. Here, we report that harmaline attenuates ESCC growth by directly targeting the mammalian target of rapamycin (mTOR). Harmaline strongly reduced cell proliferation and anchorage-independent cell growth. Additionally, harmaline treatment induced G2/M phase cell-cycle arrest through upregulation of p27. The results of in vitro and cell-based assays showed that harmaline directly inhibited the activity of mTOR kinase and the phosphorylation of its downstream pathway components. Depletion of mTOR using an shRNA-mediated strategy in ESCC cell lines indicated that reduced mTOR protein expression levels are correlated with decreased cell proliferation. Additionally, we observed that the inhibitory effect of harmaline was dependent upon mTOR expression. Notably, oral administration of harmaline suppressed ESCC patient-derived tumor growth in vivo. Taken together, harmaline is a potential mTOR inhibitor that might be used for therapeutically treating ESCC.

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Section: Introductionmentioning

confidence: 99%

Harmaline isolated from Peganum harmala suppresses growth of esophageal squamous cell carcinoma through targeting mTOR

Zhang

Shi

Xie

et al. 2021

Phytotherapy Research

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“…The doses were as follows: LPS (5 mg/kg dissolved in 0.9% saline, administered via intraperitoneal (i.p.) injection) 27 , Fluoro-Gold (4% in 0.9% saline, 0.5 µl/side, administered via microinjection into the mPFC) 28 , CNO (1 mM dissolved in 10% DMSO in 0.9% saline, 0.5 µl/side, via microinjection into the mPFC) 29 , D-AP5 (1µg/µl dissolved in 10% DMSO in 0.9% saline, 0.5 µl /side, via microinjection into the mPFC) 30 , and NBQX (10 nmol/ml dissolved in 10% DMSO in 0.9% saline, 1 µl /side, via microinjection into the mPFC) 31 , according to previous studies.…”

Section: Methodsmentioning

confidence: 99%

Chemogenetic activation of the HPC-mPFC pathway improves cognitive dysfunction in lipopolysaccharide -induced brain injury

Ge¹,

Chen²,

Zhang³

et al. 2023

Theranostics

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Rationale: Although sepsis-associated encephalopathy (SAE) is a common psychiatric complication in septic patients, the underlying mechanisms remain unclear. Here, we explored the role of the hippocampus (HPC) - medial prefrontal cortex (mPFC) pathway in cognitive dysfunction in lipopolysaccharide-induced brain injury. Methods: Lipopolysaccharide (LPS, 5 mg/kg, intraperitoneal) was used to induce an animal model of SAE. We first identified neural projections from the HPC to the mPFC via a retrograde tracer and virus expression. The activation viruses (pAAV-CaMKIIα-hM3Dq-mCherry) were injected to assess the effects of specific activation of mPFC excitatory neurons on cognitive tasks and anxiety-related behaviors in the presence of clozapine-N-oxide (CNO). Activation of the HPC-mPFC pathway was evaluated via immunofluorescence staining of c-Fos-positive neurons in mPFC. Western blotting was performed to determine protein levels of synapse- associated factors. Results: We successfully identified a structural HPC-mPFC connection in C57BL/6 mice. LPS-induced sepsis induces cognitive impairment and anxiety-like behaviors. Chemogenetic activation of the HPC-mPFC pathway improved LPS-induced cognitive dysfunction but not anxiety-like behavior. Inhibition of glutamate receptors abolished the effects of HPC-mPFC activation and blocked activation of the HPC-mPFC pathway. The glutamate receptor-mediated CaMKII/CREB/BDNF/TrKB signaling pathway influenced the role of the HPC-mPFC pathway in sepsis-induced cognitive dysfunction. Conclusions: HPC-mPFC pathway plays an important role in cognitive dysfunction in lipopolysaccharide-induced brain injury. Specifically, the glutamate receptor-mediated downstream signaling appears to be an important molecular mechanism linking the HPC-mPFC pathway with cognitive dysfunction in SAE.

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“…For activation of the aIC, NMDA (0.2 or 1 μg/μl) was diluted in 0.9% normal saline. The concentration (0.1, 0.5 and 1.0 μg/side) of NMDA for activation of the aIC was determined according to previous studies [27][28][29]. However, we used lower than 1.0 μg of NMDA since our pilot study confirmed that mice were died within 10 minutes after systemic administration of 1.0 μg.…”

Section: Administration Of Drugsmentioning

confidence: 99%

“…5C). The dose was determined based on previous studies and our pilot result [27][28][29]. Although the effect of NMDA was minimal with 0.1 μg concentration, 0.5 μg NMDA significantly increased nocifensive behaviors in the second phase of formalin test (Figs.…”

Section: Nmda Microinjection Into the Aic Reverses Sdv-induced Analge...mentioning

confidence: 99%

A Critical Involvement of Glutamatergic Neurons in the Anterior Insular Cortex for Subdiaphragmatic Vagotomy-induced Analgesia

et al. 2023

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Subdiaphragmatic vagotomy (SDV) is known to produce analgesic effect in various pain conditions including not only visceral pain but also somatic pain. We aimed to determine brain mechanisms by which SDV induces analgesic effect in somatic pain condition by using formalin-induced acute inflammatory pain model. We identified brain regions that mediate SDV-induced analgesic effect on acute inflammatory pain by analyzing c-Fos expression in the whole brain. We found that c-Fos expression was specifically increased in the anterior insular cortex (aIC) among subregions of the insular cortex in acute inflammatory pain, which was reversed by SDV. These results were not mimicked in female mice, indicating sexualdimorphism in SDV-induced analgesia. SDV decreased c-Fos expressions more preferentially in glutamatergic neurons rather than GABAergic neurons in the aIC, and pharmacological activation of glutamatergic neurons with NMDA in the aIC inhibited SDV-induced analgesic effect. Furthermore, chemogenetic activation of glutamatergic neurons in the aIC reversed SDV-induced analgesia. Taken together, our results suggest that the decrease in the neuronal activity of glutamatergic neurons in the aIC mediates SDV-induced analgesic effect, potentially serving as an important therapeutic target to treat inflammatory pain.

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Potentiation of morphine-induced antinociception by harmaline: involvement of μ-opioid and ventral tegmental area NMDA receptors

Cited by 8 publications

References 72 publications

Harmaline isolated from Peganum harmala suppresses growth of esophageal squamous cell carcinoma through targeting mTOR

Harmaline isolated from Peganum harmala suppresses growth of esophageal squamous cell carcinoma through targeting mTOR

Chemogenetic activation of the HPC-mPFC pathway improves cognitive dysfunction in lipopolysaccharide -induced brain injury

A Critical Involvement of Glutamatergic Neurons in the Anterior Insular Cortex for Subdiaphragmatic Vagotomy-induced Analgesia

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