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Novel opioid-neurotensin-based hybrid peptide with spinal long-lasting antinociceptive activity and a propensity to delay tolerance development

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Acta Pharmaceutica Sinica B 2020年第8期10卷 1440-1452页

作者： Karolina Fra˛czek Mattia Ferraiolo Emmanuel Hermans Magdalena Bujalska-Zadrozny Kaja Kasarello Anna Erdei Kamila Kulik Agnieszka Kowalczyk Piotr Wojciechowski Dorota Sulejczak Piotr Sosnowski Sebastian Granica Sandor Benyhe Katarzyna Kaczynska Lukasz Nagraba Artur Stolarczyk Agnieszka Cudnoch-Jedrzejewska Patrycja Kleczkowska Department of Pharmacodynamics Centre for Preclinical Research(CBP)Medical University of WarsawWarsaw 02-097Poland Laboratory of Neuropharmacology Institute of NeurosciencesUniversite´Catholique de LouvainBrussels B-1200Belgium Department of Experimental and Clinical Physiology Centre for Preclinical Research(CBP)Medical University of WarsawWarsaw 02-097Poland Institute of Biochemistry Biological Research CentreHungarian Academy of SciencesSzeged H-6701Hungary Doctoral School of Therotecical Medicine University of SzegedSzeged H-6720Hungary Department of Respiration Physiology Mossakowski Medical Research CentrePolish Academy of SciencesWarsaw 02-106Poland Department of Experimental Pharmacology Mossakowski Medical Research CenterPolish Academy of SciencesWarsaw 02-106Poland Department of Neuropeptides Mossakowski Medical Research CentrePolish Academy of SciencesWarsaw 02-106Poland Department of Pharmacognosy and Molecular Basis of Phytotherapy Faculty of PharmacyMedical University of WarsawWarsaw 02-097Poland Department of Orthopaedics and Rehabilitation Medical University of WarsawWarsaw 04-749Poland

The behavioral responses exerted by spinal administration of the opioid-neurotensin hybrid peptide, PK23, were studied in adult male rats. The antinociceptive effect upon exposure to a thermal stimulus, as well as tolerance development, was assessed in an acute pain model. The PK23 chimera at a dose of 10 nmol/rat produced a potent pain-relieving effect, especially after its intrathecal administration. Compared with intrathecal morphine, this novel compound was found to possess a favourable side effect profile characterized by a reduced scratch reflex, delayed development of analgesic tolerance or an absence of motor impairments when given in the same manner, though some animals died following barrel rotation as a result of its i.c.v. administration(in particular at doses higher than 10 nmol/rat). Nonetheless, these results suggest the potential use of hybrid compounds encompassing both opioid and neurotensin structural fragments in pain management. This highlights the enormous potential of synthetic neurotensin analogues as promising future analgesics.

关键词： opioid neurotensin doses

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Control of Emotion and Wakefulness by neurotensinergic Neurons in the Parabrachial Nucleus

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Neuroscience Bulletin 2023年第4期39卷 589-601页

作者： Jingwen Chen Noam Gannot Xingyu Li Rongrong Zhu Chao Zhang Peng Li Fundamental Research Center Shanghai Yangzhi Rehabilitation HospitalSchool of Life Sciences and TechnologyTongji UniversityShanghai201619China Life Sciences Institute University of MichiganAnn ArborMI48109USA Department of Biologic and Materials Sciences School of DentistryUniversity of MichiganAnn ArborMI 48109USA Department of Molecular and Integrative Physiology School of MedicineUniversity of MichiganAnn ArborMI 48109USA

The parabrachial nucleus(PBN)integrates interoceptive and exteroceptive information to control various behavioral and physiological processes including breathing,emotion,and sleep/wake regulation through the neural circuits that connect to the forebrain and the brainstem.However,the precise identity and function of distinct PBN subpopulations are still largely unknown.Here,we leveraged molecular characterization,retrograde tracing,optogenetics,chemogenetics,and electrocortical recording approaches to identify a small subpopulation of neurotensin-expressing neurons in the PBN that largely project to the emotional control regions in the forebrain,rather than the medulla.Their activation induces freezing and anxiety-like behaviors,which in turn result in tachypnea.In addition,optogenetic and chemogenetic manipulations of these neurons revealed their function in promoting wakefulness and maintaining sleep architecture.We propose that these neurons comprise a PBN subpopulation with specific gene expression,connectivity,and function,which play essential roles in behavioral and physiological regulation.

关键词： Parabrachial nucleus neurotensin Anxiety Sleep Wakefulness Breathing Neural circuit Freezing Medulla

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neurotensin receptor 1 overexpression in inflammatory bowel diseases and colitis-associated neoplasia

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World Journal of Gastroenterology 2013年第28期19卷 4504-4510页

作者： Xianyong Gui Shuhong Liu Yuchu Yan Zuhua Gao Calgary Laboratory Services and Department of Pathology and Laboratory Medicine University of Calgary Calgary Alberta T2N 2T9 Canada

AIM: To explore the association of neurotensin receptor 1 (NTSR1) with inflammatory bowel diseases (IBD) and colitis-associated neoplasia. METHODS: NTSR1 was detected by immunohistochemistry in clinical samples of colonic mucosa with IBD colitis, colitis-associated raised low-grade dysplasia (LGD) including dysplasia-associated lesions or masses (DALMs, n = 18) and adenoma-like dysplastic polyps (ALDPs, n = 4), colitis-associated high-grade dysplasia (HGD, n = 11) and colitis-associated colorectal carcinoma (CACRC, n = 13), sporadic colorectal adenomatous polyp (SAP, n = 17), and sporadic colorectal carcinoma (SCRC, n = 12). The immunoreactivity of NTSR1 was semiquantitated (as negative, 1+, 2+, and 3+) and compared among different conditions.RESULTS: NTSR1 was not detected in normal mucosa but was expressed similarly in both active and inactive colitis. LGD showed a significantly stronger expression as compared with non-dysplastic colitic mucosa, with significantly more cases showing > 2+ intensity (68.75% in LGD vs 32.26% in nondysplastic mucosa, P = 0.001). However, no significant difference existed between DALMs and ALDPs. CACRC and HGD showed a further stronger expression, with significantly more cases showing 3+ intensity than that in LGD (61.54% vs 12.50% for CACRC vs LGD, P = 0.022; 58.33% vs 12.50% for CACRC/HGD vs LGD, P = 0.015). No significant difference existed between colitis-associated and non-colitic sporadic neoplasia. CONCLUSION: NTSR1 in colonic epithelial cells is overexpressed in IBD, in a stepwise fashion with sequential progress from inflammation to dysplasia and carcinoma.

关键词： neurotensin neurotensin receptor Inflammatory bowel diseases Dysplasia Colitis-associated neoplasia Dysplasia-associated lesion or mass Sporadic adenoma Colorectal carcinoma

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neurotensin Receptor 1 (NTSR1) Overexpression in Breast Carcinomas Is Common and Independent of ER/PR/Her2 Expression

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Journal of Cancer Therapy 2013年第7期4卷 12-17页

作者： Xianyong Gui Shuhong Liu Ziran Meng Zu-Hua Gao Calgary Laboratory Services Department of Pathology and Laboratory Medicine University of Calgary Calgary Canada Calgary Laboratory Services Department of Pathology and Laboratory Medicine University of Calgary Calgary Canada Department of Pathology McGill University Montreal Canada

neurotensin (NT) is a 13-amino acid peptide with trophic effects on some neoplasms. Its bioactivities are mainly mediated by neurotensin receptor 1 (NTSR1). Both NT and NTSR1 were found to be upregulated in breast cancer. NT/NTSR1 thus becomes a potential therapeutic target. We studied whether any correlation exists between the expression of NTSR1 in breast carcinomas and the expression of ER, PR, and Her2. A total 85 cases of invasive ductal (62) and lobular (23) breast carcinomas were studied. Based on their ER/PR profiles, the ductal carcinomas (DCs) were subcategorized into ER+/PR+ (21), ER+/PR﹣ (20), and ER﹣/PR﹣ (21). All of the lobular carcinomas (LCs) were ER+/PR+. 21.57% of all DCs and 5.56% of LCs were Her2 positive. 77.78% of ER﹣/PR﹣ DCs were also Her2 negative (triple negative). The expression of NTSR1 was detected by immunohistochemistry and was semiquantitated (as negative, 1+, 2+, 3+). Both 2+ and 3+ were collectively defined as overexpression. The expression of NTSR1 was weak and focal in non-neoplastic mammary epithelial cells. It is increased in 74.19% of DCs (80.95% in ER+/PR+, 75% in ER+/PR﹣, and 66.67% in ER﹣/PR﹣ group), and in 95.65% of LCs. The overexpression of NTSR1 is similar between ER+ DCs and ER﹣ DCs (75% vs 66.67%, p > 0.05) as well as between PR+ DCs and PR﹣ DCs (80.95% in ER+/PR+ DCs vs 75% in ER+/PR﹣ DCs, p > 0.05). And it was seen in 77.78% of Her2+ DCs, 78.38% of Her2﹣ DCs, 94.12% of Her2﹣ LCs, and 78.57% of triple negative DCs. Overall, NTSR1 is commonly overexpressed in both ductal and lobular breast carcinomas and is independent of the ER/PR/Her2 profiles of the tumors. The present data supports the potential benefit of developing NTSR1 blockers in the adjuvant therapy of breast carcinomas, particularly for those “triple negative” tumors.

关键词： neurotensin neurotensin Receptor NTSR1 Breast Carcinoma Estrogen Receptor Progesterone Receptor Her2

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Clinical Significance and Detection of Neuro-Peptide and neurotensin in Patient s with Brain Glioma

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中国组织工程研究 2001年第8期15卷 155-157页

作者：尹秋霞司永兵齐法莲 General Hospital of Jinan Military Region

Objective To investigate the change of neuropeptide Y(NPY)and neurotens in(NT)in pqtients with brain glioma.Method The concentration of NPY and NT in an d around brain glioma tissue and plasma were detected with inequilibrant radio－ imunology method.Result NPY concentrqtion in brain glioma tissue was obviously h igher than that in tissue around the tumor(P<0.01).The Concentration of NT in br ain glioma tissue was obviously higher that in tissue around the glioma(P<0.01). Conclusion Detection of NPY and NT in brain gliom aprovides basis for further st udy on brain glioma and explainning clinical and imaginal symjptom of brain glio ma.

关键词： brain glioma neuropeptide Y neurotensin

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Effects of acute brain injury on the contents of neurotensin in brain areas,pituitary gland and plasma in rats

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Journal of Medical Colleges of PLA(China) 1993年第1期8卷 46-51页

作者：刘志敏林葆城王成海路长林赵小林 Department of Neurobiology Second Military Medical University Shanghai 200433

The changes of immunoreactive neurotensin(ir-NT)contents in the brain areas,pituitary gland and plasma in the traumatized rats were observed in the present study.The results of radioimmunoassay exhibited significant changes of the ir-NT contents inthe hypothalamus,pituitary gland,plasma,injured tissue,hippocampus,central gray andspinal cord in the posttraumatic rats at different intervals.A predominant characteristicsof the changes of ir-NT levels in the brain areas,pituitary gland and plasma was thedramatical decrease at various times except for the hypothalamus,central gray andhippocampus with biphasic alterations.The ir-NT contents in the frontal cortex andpons-medulla also displayed changes to different extent under the acute craniocerebraltrauma condition.These results suggest that NT may play a role in the pathophysiologyof traumatic head injury.

关键词： neurotensin acute brain injury radioimmunoassay animal rats

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Expression of feeding-related peptide receptors mRNA in GT1-7 cell line and roles of leptin and orexins in control of GnRH secretion

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Acta Pharmacologica Sinica 2005年第8期26卷 976-981页

作者： Ying YANG, Li-bin ZHOU, Shang-quan LIU, Jing-feng TANG, Feng-yin LI, Rong-ying LI, Huai-dong SONG, Ming-dao CHEN~2 Rui-jin Hospital Affiliated to Shanghai Second Medical University, Shanghai Institute of Endocrine and Metabolic Diseases, Shangha 200025. China Rui-jin Hospital Affiliated to Shanghai Second Medical University Shanghai Institute of Endocrine and Metabolic Diseases Shanghai China

Aim: To investigate the expression of feeding-related peptide receptors mRNA in GT1-7 cell line and roles of leptin and orexins in the control of GnRH secretion. Methods: Receptors of bombesin3, cholecystoldnin (CCK)-A, CCK-B, glucagonlike peptide (GLP)1, melanin-concentrating hormone (MCH)I, orexin1, orexin2, neuromedin-B, neuropeptide Y (NPY)1 and NPYS, neurotensin (NT)1, NT2, NT3, and leptin receptor long form mRNA in GT1-7 cells were detected by reversed transcriptase-polymerase chain reaction. GT1-7 cells were treated with leptin, orexin A and orexin B at a cohort of concentrations for different lengths of time, and GnRH in medium was determined by radioimmunoassay (RIA). Results: Receptors of bombesin 3, CCK-B, GLP1, MCH1, orexin1, neuromedin-B, NPY1, NPYS, NT1, NT3, and leptin receptor long form mRNA were expressed in GT1-7 cells, of which, receptors of GLP1, neuromedin-B, NPY1, and NT3 were highly expressed. No amplified fragments of orexin2, NT2, and CCK-A receptor cDNA were generated with GT1-7 RNA, indicating that the GT1-7 cells did not express mRNA of them. Leptin induced a significant stimulation of GnRH release, the results being most significant at 0.1 nmol/L for 15 min. In contrast to other studies in hypothalamic explants, neither orexin A nor orexin B affected basal GnRH secretion over a wide range of concentrations ranging from 1 nmol/L to 500 nmol/Lat 15, 30, and 60 min. Conclusion: Feeding and reproductive function are closely linked. Many orexigenic and anorexigenic signals may control feeding behavior as well as alter GnRH secretion through their receptors on GnRH neurons.

关键词： GT1-7 cell line bombesin cholecystokinin neuropeptide Y neurotensin orexin leptin gonadorelin

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neurotensin expressed by glioma-initiating cells affects clinical outcome in glioma patients

Neurotensin expressed by glioma-initiating cells affects cli...

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中国神经科学学会第九届全国学术会议暨第五次会员代表大会

作者： Liang YI~1,Hualiang XIAO~2,Minhui XU~3,Tunan CHEN~1,Fei LI~1,Mei LI~1,Chunxia LUO~1,Mingyue ZHAO~1, Hua FENG~(1,*) 1 Department of Neurosurgery,Southwest Hospital,Third Military Medical University,Chongqing,China 2 Department of Pathology,Daping Hospital,Third Military Medical University,Chongqing,China 3 Department of Neurosurgery,Daping Hospital,Third Military Medical University,Chongqing,China

＜正＞Malignant glioma is the most common and fatal tumor in central nervous system,with the poor prognosis even with the advanced treatments.Seeking new prognostic factors and molecular targets may contribute to the understanding of malignance progression and patient treatment.Here,we investigated the neurotensin（Nts） expression in a series of 116 patients with gliomas of different histology grades and primary cultured glioma initiating cells （GICs）.The correlation between Nts expression and the prognosis was analyzed.The effect of Nts expression on GICs proliferation was also detected.We found that NTS expression was detected in 70.9%of malignant gliomas and was significantly（P = 0.015） related with a poor prognosis.Multivariate analysis indicated that Nts expression（P = 0.007） was independent predictors of poor prognosis.Meanwhile,the results revealed that Nts was mainly expressed by GICs, not by differentiated glioma cells.Inhibition of Nts expression resulted in a significant reduction of GICs proliferation. Our study indicated that the expression of Nts positively correlated with the histology grades of malignances and could be identified as a prognostic marker in patients with glioma.Nts which are highly expressed in GICs promoted the proliferation of GICs in an autocrine fashion and might be a potential target to restrict self-renewal of GICs.

关键词： neurotensin glioma stem cells glioma prognosis marker

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neurotensin expressed by glioma-initiating cells affects clinical outcome in glioma patients

Neurotensin expressed by glioma-initiating cells affects cli...

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2011中华医学会神经外科学学术会议

作者： Liang Yi1 ,2 Minhui Xu1 Hua Feng2 1.Department of Neurosurgery, Daping Hospital, Third Military Medical University, Chongqing, 4 0004 2 , China 2.Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Chongqing, 4 0004 2 , China

Objective Malignant glioma is the most common and fatal tumor in central nervous system, with the poor prognosis even with the advanced treatments. Seeking new prognostic factors and molecular targets may contribute t... 详细信息

关键词： neurotensin glioma cancer stem cells

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Effects of neurotensin on expression of opioid receptors:An experimental study

Effects of neurotensin on expression of opioid receptors:An ...

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中国神经科学学会第十届全国学术会议

作者： Hai-Qing LIU Jing CHEN Bo BAI School of life science Shandong Agricultural University Department of physiology Taishan Medical College Department of neurobiology Jining Medical College

Objective In the central nervous system,the opioids transmitter and non-opioids transmitter system jointly complete multiple pathophysiological process.Many studies indicated that neurotensin can effectively increase the threshold of pain,and enhance analgesia induced by morphine or acupuncture.This study is to explore the experimental evidence for partially explaining the mechanisms of neurotensin analgesia and neurotensin-enhanced acupuncture analgesia at molecular and receptor levels.Methods The neuron model of rat caudate putmen culture in vitro was used to examine the effects of neurotensin and/or morphine on the expression of opioid receptors mRNA.The possibility of heterodimerization between between neurotensin receptor and kappa opioid receptor was identified by bioluminescence resonance energy transfer assay.Mouse tail reaction test was carried out to examine the effects of neurotensin on the mouse tail erection induced by morphine,and investigate the effects of neurotensin on the morphine addictive ethology.Results neurotensin(10 mol/L) promoted but morphine(10 mol/L) reduced the mu opioid receptor gene expression.When the cells incubated by neurotensin(10 or 10 mol/L) plus morphine,the inhibition of mu opioid receptor by morphine was almost missing.While both neurotensin and morphine increased the kappa opioid receptor gene expression.In 293 cells,neurotensin receptor interacted with kappa opioid receptor.In mouse tail reaction test,mice were signignificantly marked by tail erection,continuously running and jumping after injection of morphine(15 mg/kg).However,the mouse tail reactions were inhibited to some extent after pretreated with 100 μg/kg or more of NT.After morphine injection in the mice pretreated with neurotensin 300 μg/kg,no tail reaction was noted,and the mice appeared to be quiet and less active.Conclusion There was a certain paralleled correlation between mouse tail reaction and the addiction of narcotic analgesia.Morphine has a strong addiction,so the mice have a higher tail erection ind

关键词： neurotensin morphine opioid receptor addiction

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