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1.
Eur J Pharmacol ; : 174139, 2021 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-33933465

RESUMO

Burn injury is one of the main causes of mortality worldwide and frequently associated with severe and long-lasting pain that compromises the quality of patient life. Several studies have shown that the mu-opioid system plays an important role in burn pain relief. In this study, we investigated the spinal antinociception induced by the endogenous mu-opioid receptor (MOR) agonists endomorphins and explored their mechanisms of actions in burn injury-induced pain model. Our results showed that intrathecal injection of endomorphin-1 and -2 dose-dependently attenuated mechanical allodynia and thermal hyperalgesia via the mu-opioid receptor in mice on day 3 after burn injury, which was consistent with the data obtained from the mu-opioid receptor knockout mice. Western blot showed that the phosphorylation levels of extracellular signal-regulated kinase1/2 (ERK1/2) and p38 mitogen-activated protein kinase (p38 MAPK) in ipsilateral spinal cord tissues were significantly up-regulated after burn injury. Intrathecal injection of endomorphins selectively inhibited the activation of p38 MAPK on day 3 after burn injury via the mu-opioid receptor. Further studies found that repeated application of the specific p38 MAPK inhibitor SB203580 dose-dependently inhibited burn-injury pain, as well as the activation of spinal p38 MAPK. Taken together, our present study demonstrates that intrathecal injection of endomorphins attenuates burn-injury pain in male mice by affecting the spinal activation of p38 MAPK via the mu-opioid receptor.

2.
Food Chem ; 357: 129744, 2021 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-33878579

RESUMO

Cooking performance, micro- and molecular structure, storage stability and shelf-life prediction of high-moisture wet starch noodles (SN) were investigated. SEM images revealed that compared to dried SN, cooked wet SN had more evenly honeycomb-like network with smaller size of pores, indicating stronger interaction among molecules and causing favorable cooking performance. XRD and ATR-FTIR results evidenced that wet SN contained more complete crystallites and higher proportion of crystalline region. During storage, the quality decay of wet SN was mainly associated to the increment of total aerobic viable count (TAVC), titrable acidity and amylase, as well as the decreased textural hardness, overall acceptability and lightness. Based on TAVC, titrable acidity and overall acceptability, predicted shelf-life of vacuum-packed wet SN at 25 °C was 15.31, 21.54 and 16.65 weeks respectively, with relative error all within 20%, proving that the validated model could be an effective tool for monitoring the shelf-life of wet SN.

3.
J Pediatr ; 2021 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-33631166

RESUMO

OBJECTIVES: To investigate the efficacy and safety of sirolimus in the treatment of cardiac rhabdomyomas associated with tuberous sclerosis complex and the specific benefits in different subgroups. STUDY DESIGN: The study was a prospective cohort and self-controlled case series study. Based on the prevalence of cardiac rhabdomyoma at different ages, we estimated the natural tumor disappearance rate. The subgroup analysis was done by Cox regression. Self-controlled case series method was used to assess the magnitude and duration of the drug effect. Adverse events were described. RESULTS: A total of 217 patients were included in the cohort study. Tumor disappearance rate was higher in younger age groups (hazard ratio = 0.99, P = .027) and female patients (hazard ratio = 2.08, P = .015). The age-adjusted incidence ratio showed that the disappearance of rhabdomyomas between 3 and 6 months was more related to sirolimus. Adverse events were observed 60 times in 42 of 217 children, mainly stomatitis. CONCLUSIONS: Sirolimus can increase the disappearance rate of cardiac rhabdomyoma in the tuberous sclerosis complex population. Efficacy varies by sex and age: female and younger patients have higher tumor disappearance rate. Sirolimus is well-tolerated.

4.
J Agric Food Chem ; 2021 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-33435687

RESUMO

Omega-7 (n-7) phospholipids were bioactive substances in marine animals. In this study, a fast lipidomics phenotyping approach for real-time in situ screening of n-7 phospholipids in five kinds of economic seafood, salmon, prawn, bluefin tuna, hairtail, and butterfish, was established using iKnife rapid evaporative ionization mass spectrometry (REIMS). The n-7 phospholipids were structurally characterized and quantitatively analyzed, and the profiles were statistically analyzed by multivariate recognition analysis. It indicated that the difference of n-7 phospholipids in seafood samples was significant (p < 0.05), with R2(cum) and Q2(cum) values of >0.9. The proportion of n-7 phospholipids in salmon was the highest (20.43%), followed by bluefin tuna, prawn, hairtail, and butterfish. The ions of m/z 742.54 (PC 16:1-18:1), 768.55 (PC 16:1-20:2), 697.48 (PE 16:1-18:1), and 699.48 (PE 16:1-18:0) were the main n-7 phospholipids. The effectiveness of iKnife REIMS was further verified by hydrophilic interaction chromatography mass spectrometry and gas chromatography. The results demonstrated that proposed iKnife REIMS was an excellent technique for front-line screening of n-7 phospholipids in a large variety of marine biological resources.

5.
J Med Chem ; 2020 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-33271020

RESUMO

In a previously described chimeric peptide, we reported that the multifunctional opioid/neuropeptide FF (NPFF) receptor agonist 0 (BN-9) produced antinociception for 1.5 h after supraspinal administration. Herein, four cyclic disulfide analogs containing l- and/or d-type cysteine at positions 2 and 5 were synthesized. The cyclized analogs and their linear counterparts behaved as multifunctional agonists at both opioid and NPFF receptors in vitro and produced potent analgesia without tolerance development. In comparison to 0, cyclized peptide 6 exhibited sevenfold more potent µ-opioid receptor agonistic activity in vitro. Interestingly, the cyclized analog 6 possessed an improved stability in the brain and an increased blood-brain barrier permeability compared to the parent peptide 0 and produced more potent analgesia after supraspinal or subcutaneous administration with improved duration of action of 4 h. In addition, antinociceptive tolerance of analog 6 was greatly reduced after subcutaneous injection compared to fentanyl, as was the rewarding effect, withdrawal reaction, and gastrointestinal inhibition.

6.
Food Res Int ; 137: 109408, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33233095

RESUMO

Clam (Corbicula fluminea) contains significant amount of phospholipids, and the profile of phospholipids could be used as an index for nutrition evaluation. In this study, a titania-coated fibrous silica (TiO2/KCC-1) core-shell microsphere based solid-phase extraction (SPE) and hydrophilic interaction liquid chromatography mass spectrometry (HILIC-MS) method was developed to study the phospholipids in clam. The structure and morphology of TiO2/KCC-1 were characterized by transmission electron microscopy (TEM), scanning electron microscope (SEM), X-ray diffraction (XRD), and ultraviolet-visible diffuse reflectance spectroscopy (UV-vis DRS). The analytical results indicated that the phospholipid molecular species (PMS) could be extracted in a cleaner manner after TiO2/KCC-1 SPE, benefiting from the enhanced signals and decreased MS noise of phospholipids. Based on the principal component analysis (PCA) and partial least squares regression discriminant analysis (PLS-DA) models, the PMS with the most obvious beneficiaries of TiO2/KCC-1 SPE were identified, e.g. PC 16:0/20:5 (m/z 824.6), PC 16:0/22:6 (m/z 850.6), PE 18:1/18:2 (m/z 740.4), and PE 18:0/22:6 (m/z 790.5). Finally, the proposed method was validated to be sensitive and precise. This study provides an efficient tool to analyze the phospholipids in clam and the prospect to use this method for future applications in various samples.

7.
Artigo em Inglês | MEDLINE | ID: mdl-33136722

RESUMO

BACKGROUND: Ischemic colitis (IC) was investigated to be associated with dyslipidemia and subcutaneous adipose tissue. Nonalcoholic fatty liver disease (NAFLD) is associated with ischemic diseases such as coronary heart disease, ischemic stroke. But there is a paucity of data regarding the association between NAFLD and IC. NAFLD may be associated with the treatment and prognosis of IC. We investigated risk factors and characteristics associated with NAFLD in patients with IC. METHODS: Patients with IC (NAFLD: 34 and controls: 81) from Zhongnan Hospital were investigated retrospectively from January 2012 to December 2018. Clinical data were compared by chi-square tests or independent samples T-tests. Binary logistic regressions and Kaplan-Meier analysis were performed to evaluate risk factors and prognosis, respectively. RESULTS: NAFLD was diagnosed in 28.19% patients with IC. In the logistic regression analysis, hypertension [odds ratio (OR) 3.523; P = 0.019], elevated alanine aminotransferase (ALT) (OR 6.278; P = 0.048), elevated triglyceride (OR 4.667; P = 0.003) and increased weight (OR 1.055; P = 0.039) were risk factors of NAFLD in patients with IC. Patients with NAFLD were more likely to require the vasodilators (P = 0.011) and get a relapse of IC (P = 0.011). CONCLUSION: NAFLD was found in 28.19% of patients with IC. Hypertension, increased weight, elevated ALT and triglyceride are independent predictors of NAFLD in patients with IC. NAFLD in patients with IC is associated with a greater probability of requiring for the vasodilators. NAFLD in IC and period of bowel rest are risk factors for the recurrence of IC.

8.
Artigo em Inglês | MEDLINE | ID: mdl-33136724

RESUMO

The main symptoms of coronavirus disease 2019 (COVID-19) are respiratory manifestations, while some confirmed patients developed gastrointestinal symptoms or even initially presented digestive symptoms. The link between pneumonia and gastrointestinal symptoms caused by severe acute respiratory symptoms coronavirus 2 focused our attention on the concept of 'gut-lung axis'. In this review, we discuss the inevitability and possible mechanisms of the occurrence of intestinal symptoms or intestinal dysfunction in COVID-19 from the perspective of the gut-lung axis, as well as the influence of the imbalance of intestinal homeostasis on the respiratory symptoms of COVID-19. The interaction between lung and intestine might lead to a vicious cycle of pulmonary and intestinal inflammation which may be a potential factor leading to the death of patients with COVID-19.

9.
Am J Med Genet A ; 2020 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-33205896

RESUMO

Developmental and epileptic encephalopathy (DEE) is a severe encephalopathy in infants and early childhood. In this study we reported a recurrent de novo variant (c.3985C>T, p.R1330W) in HECW2 (HECT, C2 and WW domain containing E3 ubiquitin protein ligase 2) (MIM# 617245) identified by screening 240 patients with DEE and summarized clinical features of published DEE patients with HECW2 variants. Functionally, transcriptional knockdown of zebrafish hecw2a led to early morphological abnormalities in the brain tissues. These results suggest a potential functional link between HECW2 dysfunction and brain development.

10.
Pharmacol Res ; 161: 105228, 2020 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-33027714

RESUMO

Fatty acid transport protein 2 (FATP2) is a multifunctional protein whose specific function is determined by the type of located cell, its intracellular location, or organelle-specific interactions. In the different diseases setting, a newfound appreciation for the biological function of FATP2 has come into view. Two main functions of FATP2 are to activate long-chain fatty acids (LCFAs) as a very long-chain acyl-coenzyme A (CoA) synthetase (ACSVL) and to transport LCFAs as a fatty acid transporter. FATP2 is not only involved in the occurrence of nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM), but also plays an important role in lithogenic diet-induced cholelithiasis, the formation of cancer tumor immunity, the progression of chronic kidney disease (CKD), and the regulation of zoledronate-induced nephrotoxicity. Herein, we review the updated information on the role of FATP2 in related diseases. In particular, we discuss the new functions of FATP2 and propose that FATP2 is a potential clinical biomarker and therapeutic target. In conclusion, regulatory strategies for FATP2 may bring new treatment options for cancer and lipid metabolism-related disorders.

11.
Cancer Cell Int ; 20: 510, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33088218

RESUMO

Background: Due to the high morbidity and poor clinical outcomes, early predictive and prognostic biomarker identification is desiderated in colorectal cancer (CRC). As a homologue of the Deleted in Colorectal Cancer (DCC) gene, the role of Neogenin-1 (NEO1) in CRC remained unveiled. This study was designed to probe into the effects and potential function of NEO1 in CRC. Methods: Online databases, Gene Set Enrichment Analysis (GSEA), quantitative real-time PCR and western blotting were used to evaluate NEO1 expression in colorectal cancer tissues. Survival analysis was performed to predict the prognosis of CRC patients based on NEO1 expression level. Then, cell proliferation was detected by colony formation and Cell Counting Kit 8 (CCK-8) assays. CRC cell migration and invasion were examined by transwell assays. Finally, we utilized the Gene Set Variation Analysis (GSVA) and GSEA to dig the potential mechanisms of NEO1 in CRC. Results: Oncomine database and The Cancer Genome Atlas (TCGA) database showed that NEO1 was down-regulated in CRC. Further results validated that NEO1 mRNA and protein expression were both significantly lower in CRC tumor tissues than in the adjacent tissues in our clinical samples. NEO1 expression was decreased with the progression of CRC. Survival and other clinical characteristic analyses exhibited that low NEO1 expression was related with poor prognosis. A gain-of-function study showed that overexpression of NEO1 restrained proliferation, migration and invasion of CRC cells while a loss-of-function showed the opposite effects. Finally, functional pathway enrichment analysis revealed that NEO1 low expression samples were enriched in inflammation-related signaling pathways, EMT and angiogenesis. Conclusion: A tumor suppressor gene NEO1 was identified and verified to be correlated with the prognosis and progression of CRC, which could serve as a prognostic biomarker for CRC patients.

12.
Cancer Biol Med ; 17(3): 555-568, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32944390

RESUMO

In the interaction between a tumor and the immune system, immune checkpoints play an important role, and in tumor immune escape, co-inhibitory immune checkpoints are important. Immune checkpoint inhibitors (ICIs) can enhance the immune system's killing effect on tumors. To date, impressive progress has been made in a variety of tumor treatments; PD1/PDL1 and CTLA4 inhibitors have been approved for clinical use in some tumors. However, glioblastoma (GBM) still lacks an effective treatment. Recently, a phase III clinical trial using nivolumab to treat recurrent GBM showed no significant improvement in overall survival compared to bevacizumab. Therefore, the use of immune checkpoints in the treatment of GBM still faces many challenges. First, to clarify the mechanism of action, how different immune checkpoints play roles in tumor escape needs to be determined; which biomarkers predict a benefit from ICIs treatment and the therapeutic implications for GBM based on experiences in other tumors also need to be determined. Second, to optimize combination therapies, how different types of immune checkpoints are selected for combined application and whether combinations with targeted agents or other immunotherapies exhibit increased efficacy need to be addressed. All of these concerns require extensive basic research and clinical trials. In this study, we reviewed existing knowledge with respect to the issues mentioned above and the progress made in treatments, summarized the state of ICIs in preclinical studies and clinical trials involving GBM, and speculated on the therapeutic prospects of ICIs in the treatment of GBM.

14.
Int J Colorectal Dis ; 35(9): 1651-1661, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32666290

RESUMO

PURPOSE: There is a growing literature on the significance of tumor-associated macrophages (TAMs) in colorectal cancer (CRC). However, the role of TAMs in predicting the prognosis of CRC remains controversial. The current study aims to determine the prognostic and clinicopathological value of different types and distribution of TAMs in CRC. METHODS: A comprehensive literature search of PubMed, Embase, and Cochrane Library databases was conducted from the inception to 1 September 2019. The correlations of TAMs with overall survival (OS), disease-free survival (DFS), cancer-specific survival (CSS), and clinicopathological characteristics were analyzed. RESULTS: A total of 5,575 patients from 29 studies were included in this meta-analysis. The pooled hazard ratios (HRs) indicated that high density of pan-macrophages in tumor invasive margin (IM) was associated with better OS (HR = 0.57, 95%CI = 0.38-0.85), DFS (HR = 0.32, 95%CI = 0.19-0.52), and CSS (HR = 0.56, 95%CI = 0.41-0.77). Moreover, the high density of pan-macrophages in tumor center (TC) was correlated with better DFS (HR = 0.66, 95%CI = 0.45-0.96). However, high expression of M2 macrophages in TC was associated with poor DFS (HR = 2.42, 95%CI = 1.45-4.07) and CSS (HR = 1.74, 95%CI = 1.24-2.44). High M2 macrophages density in IM was also associated with short DFS (HR = 2.81, 95%CI = 1.65-4.77). In addition, the results showed that high density of pan-macrophages in IM was associated with no tumor metastasis, while high M2 macrophages density in TC was correlated with poor tumor differentiation. CONCLUSION: High Pan-TAMs density in IM has a positive effect on the prognosis of CRC patients, while high density M2 macrophage infiltration in TC is a strong indicator of poor prognosis.

15.
Front Immunol ; 11: 1169, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32670278

RESUMO

Nonalcoholic steatohepatitis (NASH), the advanced stage of nonalcoholic fatty liver disease (NAFLD), is emerging as a leading cause of progressive liver fibrosis and end-stage liver disease. Liver macrophages, mainly composed of Kupffer cells (KCs) and monocyte-derived macrophages (MoMFs), play a vital role in NASH progression and regression. Recent advances suggest that cell-cell communication is a fundamental feature of hepatic microenvironment. The reprogramming of cell-cell signaling between macrophages and surrounding cells contributes to the pathogenesis of NASH. In this review, we summarize the current knowledge of NASH regarding the composition of liver macrophages and their communication with surrounding cells, which are composed of hepatocytes, hepatic stellate cells (HSCs), liver sinusoidal endothelial cells (LSECs) and other immune cells. We also discuss the potential therapeutic strategies based on the level of macrophages.

16.
Neuropharmacology ; 175: 108178, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32544481

RESUMO

Pharmacological evidence indicated a functional interaction between neuropeptide FF (NPFF) and cannabinoid systems, and the cannabinoids combined with the NPFF receptor agonist neuropeptide VF (NPVF) produced antinociception without tolerance. In the present study, VF-13, a chimeric peptide containing the pharmacophores of the endogenous cannabinoid peptide VD-hemopressin(α) (VD-Hpα) and NPVF, was synthesized and pharmacologically evaluated. In vitro, VF-13 significantly upregulated the phosphorylated level of extracellular signal-regulated kinase 1/2 (ERK1/2) in CHO cells stably expressing CB1 receptors and inhibited forskolin-induced cAMP accumulation in HEK293 cells stably expressing NPFF1 or NPFF2 receptors. Moreover, VF-13 induced neurite outgrowth in Neuro 2A cells via CB1 and NPFF receptors. These results suggest that VF-13 exhibits multifunctional agonism at CB1, NPFF1 and NPFF2 receptors in vitro. Interestingly, intracerebroventricular VF-13 produced dose-dependent antinociception in mouse models of tail-flick and carrageenan-induced inflammatory pain via the TRPV1 receptor. In contrast, the reference compound (m)VD-Hpα-NH2 induced CB1 receptor-mediated supraspinal antinociception. Additionally, subcutaneous injection of (m)VD-Hpα-NH2 and VF-13 produced significant antinociception in carrageenan-induced inflammatory pain model. In the tetrad assay, our data demonstrated that VF-13 elicited hypothermia, but not catalepsy and hypoactivity after intracerebroventricular injection. Notably, VF-13 produced non-tolerance forming antinociception over 6 days treatment in both acute and inflammatory pain models. Furthermore, VF-13 had no apparent effects on gastrointestinal transit, pentobarbitone-induced sedation, food intake, and motor coordination at the supraspinal level. In summary, VF-13, a novel chimeric peptide of VD-Hpα and NPVF, produced non-tolerance forming antinociception in preclinical pain models with reduced cannabinoid-related side effects.

17.
J Cell Mol Med ; 24(15): 8803-8813, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32570281

RESUMO

Ulcerative colitis (UC) is a chronic, highly heterogeneous intestinal inflammation with changes in epithelial function and tissue damage. However, the pathogenesis is still unclear between active UC and inactive UC. Herein, weighted gene co-expression network analysis was applied to explore the gene modules related to active UC. Gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) were used to further investigate the underlying mechanism of selected genes. We found that in the blue module (r = -.72), carboxypeptidase A6 (CPA6) was chosen to validate because of its high intra-modular connectivity and module membership. In the test sets, the expression level of CPA6 was down-regulated in active UC compared with inactive UC and normal colon. Furthermore, CPA6 expression was decreased primarily in the descending colon and only in mucosa affected by active UC. The receiver operating characteristic curve indicated that CPA6 expression had a performed well in diagnosing active UC from inactive UC (area under the curve = 0.99). Importantly, anti-tumour necrosis factor (TNF) treatment (infliximab and golimumab) significantly increased the CPA6 expression. Finally, GSEA and GSVA found that extracellular matrix receptor, inflammatory response and epithelial-mesenchymal transition were highly enriched in active UC with low CPA6 expression. In conclusion, CPA6 was identified and validated as a novel potential biomarker for predicting the occurrence of active UC, probably through regulating extracellular matrix or immune response.

18.
Orphanet J Rare Dis ; 15(1): 147, 2020 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-32532290

RESUMO

OBJECTIVE: Tuberous sclerosis complex (TSC) is a rare autosomal dominant genetic disease with many manifestations, and it involves any organ. In this study, we report a TSC patient with new type skin lesions. METHODS: A 7-month-old TSC boy with multiple cutaneous nodules was admitted in our hospital. We collected the clinical data of the patient. We performed biopsy of cutaneous nodules and whole-exome sequencing in both paraffin block tissue and blood samples. RESULTS: The patient presented with a 2 month history of gradual growth multiple cutaneous nodules. He had cardiac rhabdomyoma, subependymal giant cell astrocytoma (SEGA) and hypomelanotic macules. The pathological finding of cutaneous nodules was consistent with juvenile xanthogranuloma (JXG). After 3 months of sirolimus treatment, the multiple nodules disappeared. The whole-exome sequencing identified TSC1 (c.2356C > T, p.R786*) mutation in both paraffin block tissue and blood samples. We overturned the original pathological diagnosis and finally identified JXG as a new type of skin lesions in TSC. CONCLUSION: This is the first report on the occurrence of JXG skin lesions in TSC patient. Genetic testing is necessary in JXG. These findings expand the phenotype of skin in patients with TSC and contribute to the elucidation of JXG pathogenesis and treatment.

19.
Epilepsy Res ; 164: 106349, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32446163

RESUMO

Collagen type IV, alpha-1 (COL4A1) variants can cause cerebrovascular diseases, such as porencephaly and cerebral hemorrhage, in addition to other autosomal dominant hereditary diseases. Patients with COL4A1 variants can present with epilepsy, most commonly focal epilepsy. In this paper, we present five patients, three of whom were examined by the authors, and two who were previously reported. Clinically, these five patients were characterized by the presence of West syndrome (WS), periventricular leukomalacia (PVL), and microcephaly, but none had a history of premature birth or hypoxic ischemic encephalopathy (HIE). Genetic testing results indicated that all patients had heterozygous variants of COL4A1. Genetic testing for the COL4A1 variants should be considered when a patient without a history of prematurity or HIE develops WS with PVL and microcephaly.

20.
Eur J Pharmacol ; 880: 173169, 2020 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-32416184

RESUMO

Chronic opioids treatment is impeded by the development of analgesic tolerance and opioid-induced hyperalgesia. Recent studies have shown that multi-functional opioid compounds produce analgesic activities with limited side effects. We developed a novel multi-functional peptide targeting opioid and neuropeptide FF receptors named BN-9, which produced potent and non-tolerance forming antinociceptive effect after supraspinal and systemic administrations. In the present study, the analgesic properties and potential side effects of intrathecal BN-9 were investigated in a range of preclinical rodent models. In complete Freund's adjuvant-induced inflammatory pain model, intrathecal BN-9 dose-dependently produced analgesic effect via opioid receptors, and the spinal antinociceptive effect was augmented by the neuropeptide FF receptor antagonist RF9. In contrast, in plantar incision-induced postoperative pain model, BN-9 exhibited potent anti-allodynic effect via opioid receptors and, at least partially, neuropeptide FF receptors. In mouse models of acetic acid-induced visceral pain and formalin pain, BN-9-induced spinal antinociception was mainly mediated by opioid receptors, independent of neuropeptide FF receptors. Furthermore, at the spinal level, chronic treatments with BN-9 did not lead to analgesic tolerance and cross-tolerance to morphine. Moreover, opioid-induced hyperalgesia was observed after repeated administration of morphine, but not BN-9. Taken together, our present study suggests that intrathecal BN-9 produces potent and non-tolerance forming antinociception, and does not cause opioid-induced hyperalgesia. Thus, BN-9 might serve as a promising lead compound in the development of multi-functional opioid analgesics with minimized side effects.

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