更新于：2024-11-01

μ opioid receptor

更新于：2024-11-01

基本信息

别名

hMOP、M-OR-1、MOP

+ [10]

简介

Receptor for endogenous opioids such as beta-endorphin and endomorphin (PubMed:12589820, PubMed:7891175, PubMed:7905839, PubMed:10529478, PubMed:7957926, PubMed:9689128). Receptor for natural and synthetic opioids including morphine, heroin, DAMGO, fentanyl, etorphine, buprenorphin and methadone (PubMed:12589820, PubMed:7891175, PubMed:7905839, PubMed:7957926, PubMed:10529478, PubMed:9689128, PubMed:10836142, PubMed:19300905). Also activated by enkephalin peptides, such as Met-enkephalin or Met-enkephalin-Arg-Phe, with higher affinity for Met-enkephalin-Arg-Phe (By similarity). Agonist binding to the receptor induces coupling to an inactive GDP-bound heterotrimeric G-protein complex and subsequent exchange of GDP for GTP in the G-protein alpha subunit leading to dissociation of the G-protein complex with the free GTP-bound G-protein alpha and the G-protein beta-gamma dimer activating downstream cellular effectors (PubMed:7905839). The agonist- and cell type-specific activity is predominantly coupled to pertussis toxin-sensitive G(i) and G(o) G alpha proteins, GNAI1, GNAI2, GNAI3 and GNAO1 isoforms Alpha-1 and Alpha-2, and to a lesser extent to pertussis toxin-insensitive G alpha proteins GNAZ and GNA15 (PubMed:12068084). They mediate an array of downstream cellular responses, including inhibition of adenylate cyclase activity and both N-type and L-type calcium channels, activation of inward rectifying potassium channels, mitogen-activated protein kinase (MAPK), phospholipase C (PLC), phosphoinositide/protein kinase (PKC), phosphoinositide 3-kinase (PI3K) and regulation of NF-kappa-B (By similarity). Also couples to adenylate cyclase stimulatory G alpha proteins (By similarity). The selective temporal coupling to G-proteins and subsequent signaling can be regulated by RGSZ proteins, such as RGS9, RGS17 and RGS4 (By similarity). Phosphorylation by members of the GPRK subfamily of Ser/Thr protein kinases and association with beta-arrestins is involved in short-term receptor desensitization (By similarity). Beta-arrestins associate with the GPRK-phosphorylated receptor and uncouple it from the G-protein thus terminating signal transduction (By similarity). The phosphorylated receptor is internalized through endocytosis via clathrin-coated pits which involves beta-arrestins (By similarity). The activation of the ERK pathway occurs either in a G-protein-dependent or a beta-arrestin-dependent manner and is regulated by agonist-specific receptor phosphorylation (By similarity). Acts as a class A G-protein coupled receptor (GPCR) which dissociates from beta-arrestin at or near the plasma membrane and undergoes rapid recycling (By similarity). Receptor down-regulation pathways are varying with the agonist and occur dependent or independent of G-protein coupling (By similarity). Endogenous ligands induce rapid desensitization, endocytosis and recycling (By similarity). Heterooligomerization with other GPCRs can modulate agonist binding, signaling and trafficking properties (By similarity). Does not bind agonists but may act through oligomerization with binding-competent OPRM1 isoforms and reduce their ligand binding activity. Does not bind agonists but may act through oligomerization with binding-competent OPRM1 isoforms and reduce their ligand binding activity. Couples to GNAS and is proposed to be involved in excitatory effects.

关联

246

项与 μ opioid receptor 相关的药物

Dihydrocodeine Tartrate/Chlorpheniramine Maleate/Methylephedrine Hydrochloride/Caffeine

酒石酸双氢可待因/马来酸氯苯那敏/盐酸甲基麻黄碱/咖啡因

靶点

A1R x A2aR x Adenosine receptor x H1 receptor x PDE x adrenergic receptor x μ opioid receptor

作用机制

A1R激动剂 [+6]

在研机构

SINIL PHARMACEUTICAL Co., Ltd.

原研机构

SINIL PHARMACEUTICAL Co., Ltd.

在研适应症

咳嗽

非在研适应症-

最高研发阶段批准上市

首次获批国家/地区

韩国

首次获批日期2024-08-23

Tegileridine Fumarate

富马酸泰吉利定

靶点

μ opioid receptor

作用机制

μ opioid receptor激动剂

在研机构

江苏恒瑞医药股份有限公司

原研机构

江苏恒瑞医药股份有限公司

在研适应症

术后疼痛 [+1]

非在研适应症-

最高研发阶段批准上市

首次获批国家/地区

中国

首次获批日期2024-01-30

Celecoxib/Tramadol Hydrochloride

塞来昔布/盐酸曲马多

靶点

COX-2 x μ opioid receptor

作用机制

COX-2抑制剂 [+1]

在研机构

Kowa Pharmaceuticals America, Inc.

原研机构

Esteve Pharmaceuticals S.A.

在研适应症

急性疼痛

非在研适应症

膝关节炎 [+1]

最高研发阶段批准上市

首次获批国家/地区

美国

首次获批日期2021-10-15

5,033

项与 μ opioid receptor 相关的临床试验

NCT06564857 / Not yet recruiting临床4期IIT

Remifentanil Versus Rocuronium for Optimizing Video Laryngoscopy-assisted Tracheal Intubation in Patients Undergoing General Anaesthesia - a Multicentre Randomised Controlled Trial -The ROCVIDEO Trial

Globally, we are approaching 1 million surgical procedures each day. Tracheal intubation is the mainstay of securing the patient's airway and breathing during general anaesthesia. Approximately 100.000 tracheal intubations are performed annually in Denmark. Airway management remains the primary reason for anaesthesia-related morbidity and mortality. It has been traditionally accepted that best tracheal intubation conditions are obtained by paralysing the patient's muscles, including vocal cords, using a neuromuscular blocking agent (NMBA) such as rocuronium. However, using NBMA may increase the risk of pulmonary complications, intra-operative awareness, in which the patient is paralysed but awake during surgery, anaphylaxis, and re-intubation. In addition, there is a risk of residual neuromuscular blockade postoperatively. In the US, prolonged ventilation and unplanned intubation are the top two most costly perioperative complications. An alternative to NMBA is a large dose of opioids to depress laryngeal reflexes during intubation. The most commonly used non-NMBA modality includes bolus administration of remifentanil. However, remifentanil may cause bradycardia and hypotension. Even short periods of hypotension have been shown to increase the risk of myocardial injury and other serious adverse events such as renal failure, delirium, and even mortality.
Evidence also indicates that intubation conditions using only opioids to facilitate intubation, including remifentanil, are inferior to NMBA. However, these trials are underpowered to assess effects on patient-important outcomes and are mostly at high risk of bias. A recent trial has suggested that remifentanil intubation conditions may not be very different. Almost all existing research comparing NMBA to opioids has focused on intubation conditions for direct laryngoscopy using a conventional Macintosh laryngoscopy blade. In recent years, the implementation and availability of the video laryngoscope have grown exponentially and become universal. The video laryngoscope has vastly improved the ease of tracheal intubation, and the number of failed intubations has decreased by two-thirds in Denmark, where a rapid implementation of the video laryngoscope took place. However, limited evidence exists on whether NMBA improves intubation conditions compared to remifentanil when performing video laryngoscope-assisted tracheal intubation.

开始日期2025-06-01

申办/合作机构-

NCT06574009 / Not yet recruitingN/AIIT

Better Options for Chronic Cancer Pain: a SMART Study

This proposal is relevant to the 240,000 cancer survivors who continue to use opioids long after they have successfully completed treatment for cancer at the VHA, placing them at risk of opioid addiction and overdose, and other opioid-related problems. Yet, there are no programs at the VHA to help them find alternatives to opioids, nor evidence to inform the choice of interventions. This study will meet these needs by examining four interventions that are effective at reducing opioid use in patients with chronic musculoskeletal pain but have yet to be tested in cancer survivors on long term opioid therapy. The proposed work is relevant to the VHA Pain Office's mission to provide Veterans better pain management while limiting the risks of long-term opioid therapy and it aligns with VHA Research and Development's priority to examine clinical interventions for tapering opioids. Successful completion this project will keep VHA at the forefront of the battle against the opioid epidemic with a strategy that may be adapted to address the same needs in non-Veterans.

开始日期2025-04-01

申办/合作机构

VA Office of Research and Development

NCT06237231 / Not yet recruiting临床3期

Phase III, Multicenter, Double-blind, Triple-dummy, Randomized, Parallel Clinical Trial to Evaluate the Efficacy and Safety of DIT112 in the Treatment of Moderate to Severe Pain After Dental Surgery for the Extraction of Impacted Third Molars

The purpose of this study is to evaluate the efficacy and safety of DIT112 in adolescents and adults with acute pain after dental surgery for the extraction of impacted third molars.

开始日期2025-02-15

申办/合作机构

EMS SA (Brazil)

100 项与 μ opioid receptor 相关的临床结果

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100 项与 μ opioid receptor 相关的转化医学

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0 项与 μ opioid receptor 相关的专利（医药）

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7,051

项与 μ opioid receptor 相关的文献（医药）

2025-01-01·Gene

μ-Opioid receptor transcriptional variants in the murine forebrain and spinal cord

Article

作者: Misiołek, Klaudia ; Piechota, Marcin ; Szumiec, Łukasz ; Chrószcz, Magdalena ; Korostyński, Michał ; Rodriguez Parkitna, Jan ; Radlicka-Borysewska, Anna ; Siwiec, Marcin ; Zięba, Mateusz ; Borczyk, Małgorzata ; Ziemiańska, Magdalena ; Hajto, Jacek ; Gołda, Sławomir ; Ziółkowska, Barbara

Oprm1, the gene encoding the μ-opioid receptor, has multiple reported transcripts, with a variable 3' region and many alternative sequences encoding the C-terminus of the protein. The functional implications of this variability remain mostly unexplored, though a recurring notion is that it could be exploited by developing selective ligands with improved clinical profiles. Here, we comprehensively examined Oprm1 transcriptional variants in the murine central nervous system, using long-read RNAseq as well as spatial and single-cell transcriptomics. The results were validated with RNAscope in situ hybridization. We found a mismatch between transcripts annotated in the mouse genome (GRCm38/mm10) and the RNA-seq results. Sequencing data indicated that the primary Oprm1 transcript has a 3' terminus located on chr10:6,860,027, which is ∼ 9.5 kilobases downstream of the longest annotated exon 4 end. Long-read sequencing confirmed that the final Oprm1 exon included a 10.2 kilobase long 3' untranslated region, and the presence of the long variant was unambiguously confirmed using RNAscope in situ hybridization in the thalamus, striatum, cortex and spinal cord. Conversely, expression of the Oprm1 reference transcript or alternative transcripts of the Oprm1 gene was absent or close to the detection limit. Thus, the primary transcript of the Oprm1 mouse gene is a variant with a long 3' untranslated region, which is homologous to the human OPRM1 primary transcript and encodes the same conserved C-terminal amino acid sequence.

2024-12-31·Stress

Accumbal μ-opioid receptors and salt taste-elicited hedonic responses in a rodent model of prenatal adversity, and their correlates using human functional genomics

Article

作者: Meaney, Michael J ; Bischoff, Adrianne Rahde ; Pokhvisneva, Irina ; Silveira, Patrícia P ; Mucellini, Amanda Brondani ; Levitan, Robert D ; Dalle Molle, Roberta

Prenatal adversity is associated with behavioral obesogenic features such as preference for palatable foods. Salt appetite may play a role in the development of adiposity and its consequences in individuals exposed to prenatal adversity, and sodium consumption involves individual differences in accumbal µ-opioid receptors function. We investigated the hedonic responses to salt and the levels of µ-opioid receptors and tyrosine hydroxylase in the nucleus accumbens (Nacc) of pups from an animal model of prenatal dietary restriction. In children, we evaluated the interaction between fetal growth and the genetic background associated with the accumbal µ-opioid receptor gene (OPRM1) expression on sodium consumption during a snack test. Sprague-Dawley dams were randomly allocated from pregnancy day 10 to receive an ad libitum (Adlib) or a 50% restricted (FR) diet. The pups' hedonic responses to a salt solution (NaCl 2%) or water were evaluated on the first day of life. FR and Adlib pups differ in their hedonic responses to salt, and there were decreased levels of accumbal µ-opioid and p-µ-opioid receptors in FR pups. In humans, a test meal and genotyping from buccal epithelial cells were performed in 270 children (38 intrauterine growth restricted-IUGR) at 4 years old from a Canadian prospective cohort (MAVAN). The OPRM1 genetic score predicted the sodium intake in IUGR children, but not in controls. The identification of mechanisms involved in the brain response to prenatal adversity and its consequences in behavioral phenotypes and risk for chronic diseases later in life is important for preventive and therapeutic purposes.

2024-12-31·Epigenetics

Chronic intermittent ethanol exposure-induced m6A modifications around mRNA stop codons of opioid receptor genes

Article

作者: Liu, Ying ; Zhang, Huiping ; Koo, Ji Sun

Chronic alcohol consumption may alter mRNA methylation and expression levels of genes related to addiction and reward in the brain, potentially contributing to alcohol tolerance and dependence. Neuron-like (SH-SY5Y) and non-neuronal (SW620) cells were utilized as models to examine chronic intermittent ethanol (CIE) exposure-induced global m6A RNA methylation changes, as well as m6A mRNA methylation changes around the stop codon of three opioid receptor genes (OPRM1, OPRD1, and OPRK1), which are known to regulate pain, reward, and addiction behaviours. CIE exposure for three weeks significantly increased global RNA methylation levels in both SH-SY5Y (t = 3.98, P = 0.007) and SW620 (t = 2.24, P = 0.067) cells. However, a 3-week CIE exposure resulted in hypomethylation around mRNA stop codon regions of OPRM1 and OPRD1 in both cell lines [OPRM1_(SH-SY5Y): t = -5.05, P = 0.0005; OPRM1_(SW620): t = -3.19, P = 0.013; OPRD1_(SH-SY5Y): t = -13.43, P < 0.00001; OPRD1_(SW620): t = -4.00, P = 0.003]. Additionally, mRNA expression levels of OPRM1, OPRD1, and OPRK1 were downregulated (corresponding to mRNA hypomethylation) in both SH-SY5Y and SW620 cells after a 3-week CIE exposure. The present study demonstrated that chronic ethanol exposure altered global RNA methylation levels, as well as mRNA methylation and expression levels of opioid receptor genes in both neuron-like and non-neuronal cells. Our findings suggest a potential epitranscriptomic mechanism by which chronic alcohol consumption remodels the expression of reward-related and alcohol responsive genes in the brain, thus increasing the risk of alcohol use disorder development.Abbreviations: OPRM1: the μ-opioid receptor; OPRD1: the δ-opioid receptor; OPRK1: the κ-opioid receptor; CIE: chronic intermittent ethanol exposure; CIE+WD: chronic intermittent ethanol exposure followed by a 24-hr withdrawal; SH-SY5Y: human neuroblastoma cell Line; SW620: human colon carcinoma cell line; RT-qPCR: reverse transcription followed by quantitative polymerase reaction; MazF-RT-qPCR: MazF digestion followed by RT-qPCR.

141

项与 μ opioid receptor 相关的新闻（医药）

2024-10-20

·医药观澜

12款1类新药首次在中国获批临床！来自信达生物、康弘药业、德国默克等公司

▎药明康德内容团队报道根据中国国家药监局药品审评中心（CDE）官网以及公开资料，本周（10月14日~10月20日），有近20款1类创新药首次在中国获得临床试验默示许可（IND）。本文将根据公开资料介绍其中12款新药，它们的类型包括了蛋白降解药物、基因治疗药物、CAR-T细胞治疗药物、抗体偶联药物（ADC）等等。图片来源：123RF 因诺惟康：IVB103注射液作用机制：基因治疗药物适应症：nAMD 因诺惟康公司在研的1类新药IVB103注射液获批临床，拟开发治疗新生血管性（湿性）年龄相关性黄斑变性（nAMD）。这是一款在新型载体基础上开发的一款可玻璃体内给药的眼科基因治疗药物。因诺惟康公司致力于基因编辑递送技术和药物开发，致力于解决人体所有组织和器官的基因递送问题，从而使基因治疗能被广泛地应用各种疾病和人群当中。复恩特药业：SON-DP注射液作用机制：蛋白质诱导体内原位组织重编程适应症：晚期恶性实体瘤根据复恩特药业公开资料介绍，SON-DP注射液是一款蛋白质诱导体内原位组织重编程技术药物，其有希望将癌细胞转化为正常细胞，从而治疗实体瘤。复恩特药业致力于通过将受损、病变或退化的组织细胞转化为健康的细胞，为癌症和其他重大疾病开发创新疗法。该公司开发了蛋白质诱导的原位疾病组织重编程技术，可以通过全身给予修饰转录因子蛋白，对患者体内的疾病组织中原位生成任何种类的瞬时干细胞。英矽智能：ISM6331胶囊作用机制：泛TEAD抑制剂适应症：恶性间皮瘤或其他实体瘤英矽智能申报的1类新药ISM6331胶囊获批临床，拟开发用于治疗晚期或转移性恶性间皮瘤或其他实体瘤。根据英矽智能新闻稿介绍，这是其自主研发的泛TEAD抑制剂，此前已经在美国获批临床，并获得FDA授予的孤儿药资格，用于治疗间皮瘤。ISM6331靶向转录增强相关结构域（TEAD）蛋白家族。由于TEAD对上游肿瘤信号通路的相互作用，以及对下游靶基因的控制，ISM6331作为一款药效良好的泛TEAD非共价抑制剂，有望通过调控Hippo信号通路解决抗癌药物耐药问题。华东医药、Heidelberg Pharma：HDP-101 作用机制：靶向BCMA的ADC 适应症：BCMA阳性克隆性血液学疾病由Heidelberg Pharma申报的1类新药HDP-101获批临床，拟用于治疗B细胞成熟抗原（BCMA）阳性克隆性血液学疾病（如复发/难治性多发性骨髓瘤）。公开资料显示，这是一款靶向BCMA的抗体偶联药物（ADC），由华东医药合作开发。该产品携带合成的蘑菇毒素α-鹅膏蕈碱肽衍生物amanitin作为有效载荷。Amanitin具有新的作用方式，可抑制RNA聚合酶II，有效阻止转录并诱导肿瘤细胞凋亡，无论其增殖状态如何。HDP-101此前已经获得美国FDA授予治疗多发性骨髓瘤的孤儿药资格。海创药业：HP568片作用机制：靶向ERα的蛋白降解药物适应症：ER+/HER2-乳腺癌海创药业研发的1类新药HP568片获批临床，拟开展用于治疗雌激素受体（ER）阳性和人表皮生长因子受体2（HER2）阴性的晚期乳腺癌（ER+/HER2-晚期乳腺癌）的临床试验。HP568是一款靶向降解ERα的口服蛋白降解靶向嵌合体（PROTAC）药物，由靶蛋白配体、E3连接酶配体和两配体间的连接子3部分构成。研究表明该产品对ERα野生型蛋白和临床常见的ERα突变蛋白均具有极强的降解活性。君科华元医药：HY-1608注射液作用机制：阿片μ-受体和NOP受体双重激动剂适应症：术后疼痛君科华元医药申报的1类新药HY-1608注射液获批临床，拟开发用于术后疼痛的治疗。公开资料显示，HY-1608兼有阿片μ-受体和NOP受体双重激动作用，有望研发成为一款无成瘾强效镇痛药。德国默克（Merck KGaA）：注射用M9140 作用机制：靶向CEACAM5的ADC 适应症：晚期实体瘤德国默克在研的1类新药注射用M9140获批临床。根据公示，M9140是一款抗CEACAM5抗体偶联药物（ADC），具有拓扑异构酶1 （TOP1）抑制剂有效载荷exatecan。临床前研究表明，M9140可以与CEACAM5特异性结合，选择性杀伤靶阳性癌细胞，同时还具有强大的旁观者效应。腾盛博药：注射用BRII-693 作用机制：多肽类抗生素适应症：鲍曼不动杆菌复合体和铜绿假单胞菌引起的严重感染腾盛博药（Brii Biosciences）申报的1类新药注射用BRII-693获批临床，适用于鲍曼不动杆菌复合体（ABC）和铜绿假单胞菌引起的严重感染。公开资料显示，这是一款新型脂肽抗菌药，该产品拟开发用于治疗难治性多重耐药/广泛耐药（MDR/XDR）革兰氏阴性菌感染，特别是耐碳青霉烯类鲍曼不动杆菌和耐碳青霉烯类铜绿假单胞菌感染。腾盛博药此前通过合作获得了该产品的全球独家开发和商业化协议。原启生物：OriC613注射液作用机制：双靶点Claudin 18.2/MSLN自体CAR-T细胞疗法适应症：晚期实体瘤原启生物1类新药OriC613注射液获批临床，拟开发治疗晚期实体瘤。根据原启生物新闻稿介绍，这是其自主研发的双靶点Claudin 18.2/MSLN自体CAR-T细胞治疗药物。该产品采用了创新性的双受体逻辑门控设计策略，只有在同时识别两种特定肿瘤抗原时才能激活T细胞，在增加肿瘤靶向杀伤活性的同时，能够降低非肿瘤靶向毒性（OTOT），从而提高临床安全性。华东医药：HDM2006片作用机制：HPK1蛋白降解靶向嵌合体适应症：晚期实体瘤华东医药1类新药HDM2006片获批临床，拟开发治疗晚期实体瘤。根据华东医药公告介绍，这是其首个自主研发的小分子抗肿瘤药物，为一款造血祖激酶1（HPK1）蛋白降解靶向嵌合体。HPK1位于PD-1的上游通路，是免疫细胞表达的关键激酶，有可能成为免疫治疗的下一个潜力靶点。相较于HPK1小分子抑制剂，蛋白降解剂有望大幅提升药效和安全性。信达生物：IBI3001 作用机制：B7-H3/EGFR双抗ADC 适应症：实体瘤信达生物1类新药IBI3001获批临床，拟开发治疗实体瘤。公开资料显示，IBI3001是一款潜在“first-in-class"糖基化定点偶联B7-H3/EGFR双特异性抗体偶联药物（ADC）。这是信达生物在双特异性抗体IBI334（B7-H3/EGFR双特异性抗体）基础上，使用临床验证的SyntecanE平台，将IBI334与exatecan特异性偶联，由此产生的双抗ADC新药。该产品此前已经在澳大利亚启动1期临床。康弘药业：KH629片作用机制：甲状腺激素β受体选择性激动剂适应症：MASH 康弘药业1类新药KH629片获批临床，拟开发用于治疗成人代谢功能障碍相关脂肪性肝炎（MASH）。公开资料显示，这是康弘药业自主研发的1类创新药，为一款甲状腺激素β受体（THR-β）选择性激动剂。该产品此前已经在美国获批临床。参考资料： [1]中国国家药监局药品审评中心（CDE）官网. Retrieved Oct 20，2024, From https://www.cde.org.cn/main/xxgk/listpage/4b5255eb0a84820cef4ca3e8b6bbe20c [2]各公司官网及公开资料本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权或其他合作需求，请联系wuxi_media@wuxiapptec.com。免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。

细胞疗法临床申请孤儿药免疫疗法基因疗法

2024-10-17

·生物探索

Neuron | 程龙珍团队揭示阿片类药物诱导机械痛觉敏化和镇痛耐受的中枢神经机制

引言 2024年10月14日，南方科技大学生命科学学院神经生物学系助理教授程龙珍课题组在Neuron上发表了题为Central control of opioid-induced mechanical hypersensitivity and tolerance in mice的研究论文，揭示了阿片类药物诱导机械痛觉敏化和镇痛耐受的中枢神经机制。图1（Credit: Neuron）阿片类（opioids）药物作为镇痛药已有五千多年的历史。对于中重度疼痛，目前吗啡等阿片类药物仍是临床首选的镇痛药物。然而，长期反复使用阿片类镇痛药会引起痛觉敏化（opioid induced hypersensitivity, OIH）和镇痛耐受。OIH 和镇痛耐受是临床上剂量增加和疼痛控制有限的主要原因。根据刺激的不同，OIH 和镇痛耐受可以分为机械和温度两种类型，均可进一步分为痛觉过敏（痛刺激更痛）和异常痛（非痛刺激引起的痛）。当前多项研究认为，外周伤害性感受器上的μ型阿片受体（MORs）介导了阿片类诱导的OIH和镇痛耐受，但很大程度上忽视了模态特异性（例如，机械型 vs 温度型）的机制。根据 Corder 等 2017年发表的一项研究结果，TRPV1+神经元中 MORs 的缺失可以逆转吗啡诱导的OIH 和镇痛耐受的发生，包括温度和机械两种类型（Corder et al. Nature Medicine）。其它几项研究也支持 TRPV1 伤害性感受器或外周 MORs 在介导温度和机械型 OIH 以及镇痛耐受方面的作用。根据程龙珍课题组2023年发表的一项研究工作（Du et al. Neuroscience Bulletin 2023），TRPV1 伤害感受器或外周神经系统中编码 MOR 的 Oprm1 基因缺失，或遗传学消融 TRPV1 伤害感受器，亦或消融外周表达 MOR 的神经元，都能够减弱热镇痛耐受，这与之前的研究一致；然而，尽管团队观察到延迟发生，但都不能逆转吗啡诱导的机械型痛觉敏化和镇痛耐受的诱导，尤其是触诱发痛形式。该项研究表明，外周 MORs 在 OIH 和耐受性中可能具有模态特异性作用。外周 MORs 在阿片类药物诱导的温度，而非机械型的OIH/镇痛耐受中起重要作用。本项研究聚焦探究阿片类药物诱导机械型 OIH 和镇痛耐受的中枢神经机制。已知将吗啡等阿片类药物注射到延髓头端腹内侧核（RVM）、中央导水管周围灰质（PAG）或脊髓都能起到镇痛作用。然而，团队研究人员发现，将吗啡或 MOR 激动剂 DAMGO 微注射到脑干外侧臂旁核（lateral parabrachial nucleus, lPBN），非但不能镇痛，激活 MOR 后反而引起了机械痛觉敏化。进一步，他们发现lPBN定位注射吗啡或DAMGO完全取消了吗啡全身给药的镇痛效果。根据上述结果，研究团队推测表达在lPBN的MOR可能介导了吗啡等阿片类药物诱导的机械痛觉敏化和镇痛耐受。研究团队根据此行为结果推测，表达在 lPBN 的 MORs 可能介导了吗啡等阿片类药物诱导的机械痛觉敏化和镇痛耐受。为了验证这一猜想，研究团队选择性敲除了该区域投射到下丘脑神经元上编码 MOR 的 Oprm1 基因，结果显示可完全逆转吗啡反复皮下给药诱导的机械（而非温度）型痛觉敏化和镇痛耐受。为了研究 IPBN 投射到下丘脑的神经元上 MOR 介导OIH/镇痛耐受的机制，研究人员用全细胞膜片钳电生理的方法记录了该群神经元在吗啡反复颈后皮下给药后的兴奋性变化，发现该群神经元在静息状态下的自发动作电位（sAP）的发放数目显著下降（图1）。图2：从脑干外侧臂旁核经由下丘脑再到脊髓背角的阿片类神经环路，介导吗啡等阿片类药物反复全身给药诱导的机械型痛觉敏化和镇痛耐受（Credit: Neuron）接下来，研究团队继续在多个基因工程的小鼠上，应用行为学测试和脊髓及脑片全细胞膜片钳电生理记录，结合病毒、化学遗传学、脑立体定位、免疫组化和原位杂交等研究手段证明，从脑干外侧臂旁核（lPBN）表达MOR的神经元（lPBNMOR+），到下丘脑室旁核（paraventricular hypothalamus, PVH）表达强啡肽（dynorphin, Dyn）的神经元（PVHDyn+），再到脊髓背角（spinal dorsal horn, SDH）表达κ型阿片受体（KOR）的 GABA 能神经元（SDHKOR-GABA），介导吗啡反复颈后皮下给药引起的机械（而非温度）型OIH和镇痛耐受，其机制可能是通过抑制脊髓背角“门控”对阿片类药物镇痛不敏感的机械触诱发痛神经通路的 GABA 能 Dyn 神经元（SDHDyn-GABA）。靶向操控以上从脑到脊髓的阿片类神经通路，可以完全逆转吗啡反复全身给药引起的机械痛觉敏化和镇痛耐受（图2）。该研究结果有望为解决吗啡等阿片类药物引起的疼痛相关副作用（机械痛觉敏化和镇痛耐受）提供基础理论支撑，为潜在新型药物研发和临床治疗靶点提供新思路。参考文献 https://www.cell.com/neuron/fulltext/S0896-6273(24)00662-7 责编|探索君排版|探索君文章来源|“BioArt” End 往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文 Cell | 是什么决定了细胞的大小？热文 Nature | 2024年值得关注的七项技术热文 Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文 CRISPR技术进化史 | 24年Cell综述

2024-10-07

·PRNewswire

Indivior's SUBLOCADE® Rapid Induction/Alternative Injection Site Prior Approval Supplement (PAS) Receives FDA Priority Review

PDUFA date set for February 7, 2025 If approved by the FDA, label would expand to include alternative injection sites in the thigh, buttock and back of the arm for induction and maintenance as well as rapid induction one hour after a single transmucosal buprenorphine dose; both of which address significant patient and healthcare provider unmet needs. RICHMOND, Va., Oct. 7, 2024 /PRNewswire/ -- Indivior PLC (Nasdaq/LSE: INDV) today announced the Prior Approval Supplement (PAS) for SUBLOCADE® (buprenorphine extended-release) injection submitted by Indivior, Inc. has been granted Priority Review designation by the U.S. Food and Drug Administration (FDA). The Prescription Drug User Fee Act (PDUFA) action date for this submission is set for February 7, 2025. SUBLOCADE, Indivior's monthly injectable formulation of buprenorphine for the treatment of moderate to severe opioid use disorder (OUD), is the foundation of Indivior's portfolio of innovative treatments aimed at transforming how the chronic condition of OUD is managed. This PAS seeks to further expand treatment options via two proposed updates to the SUBLOCADE label, including: Alternative Injection Sites: Expands from the current subcutaneous abdominal injection site to also include the thigh, buttock, and back of the upper arm subcutaneously for induction and maintenance. Rapid Induction Protocol: Reduces treatment induction time from the current 7-day minimum on transmucosal buprenorphine (TM BUP) to a single dose of TM BUP with 1-hour observation period to confirm tolerability. Allows for the second 300 mg dose to be administered as early as one week after the initial 300 mg injection, based on patient needs. Indivior's PAS included comprehensive data which we believe demonstrate the efficacy and safety of the new rapid induction protocol and SUBLOCADE's pharmacokinetic profile following injection at alternative sites. These updates are expected to enhance the patient experience and expand treatment access especially for those patients who, similar to the study participants, have long-term opioid use including fentanyl. A Priority Review designation means that the FDA's goal is to take action on an application within 6 months (compared to 10 months under standard review) and, if approved, would translate into significant improvements in OUD treatment with SUBLOCADE. About SUBLOCADE® SUBLOCADE ® (buprenorphine extended-release) injection, for subcutaneous use, CIII INDICATION AND HIGHLIGHTED SAFETY INFORMATION INDICATION SUBLOCADE is indicated for the treatment of moderate to severe opioid use disorder in patients who have initiated treatment with a buprenorphine-containing product, followed by dose adjustment for a minimum of 7 days. SUBLOCADE should be used as part of a complete treatment plan that includes counseling and psychosocial support. HIGHLIGHTED SAFETY INFORMATION WARNING: RISK OF SERIOUS HARM OR DEATH WITH INTRAVENOUS ADMINISTRATION; SUBLOCADE RISK EVALUATION AND MITIGATION STRATEGY Serious harm or death could result if administered intravenously. SUBLOCADE forms a solid mass upon contact with body fluids and may cause occlusion, local tissue damage, and thrombo-embolic events, including life threatening pulmonary emboli, if administered intravenously. Because of the risk of serious harm or death that could result from intravenous self-administration, SUBLOCADE is only available through a restricted program called the SUBLOCADE REMS Program. Healthcare settings and pharmacies that order and dispense SUBLOCADE must be certified in this program and comply with the REMS requirements. CONTRAINDICATIONS SUBLOCADE should not be administered to patients who have been shown to be hypersensitive to buprenorphine or any component of Indivior's proprietary buprenorphine gel depot delivery system. WARNINGS AND PRECAUTIONS Addiction, Abuse, and Misuse: SUBLOCADE contains buprenorphine, a Schedule III controlled substance that can be abused in a manner similar to other opioids. Monitor patients for conditions indicative of diversion or progression of opioid dependence and addictive behaviors. Respiratory Depression: Life threatening respiratory depression and death have occurred in association with buprenorphine. Warn patients of the potential danger of self-administration of benzodiazepines or other CNS depressants while under treatment with SUBLOCADE. Opioids can cause sleep-related breathing disorders e.g., central sleep apnea (CSA), sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. Consider decreasing the opioid using best practices for opioid taper if CSA occurs. Strongly consider prescribing naloxone at SUBLOCADE initiation or renewal because patients being treated for opioid use disorder have the potential for relapse, putting them at risk for opioid overdose. Educate patients and caregivers on how to recognize respiratory depression and how to treat with naloxone if prescribed. Risk of Serious Injection Site Reactions: The most common injection site reactions are pain, erythema and pruritus with some involving abscess, ulceration, and necrosis. The likelihood of serious injection site reactions may increase with inadvertent intramuscular or intradermal administration. Neonatal Opioid Withdrawal Syndrome: Neonatal opioid withdrawal syndrome is an expected and treatable outcome of prolonged use of opioids during pregnancy. Adrenal Insufficiency: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off the opioid. Risk of Opioid Withdrawal With Abrupt Discontinuation: If treatment with SUBLOCADE is discontinued, monitor patients for several months for withdrawal and treat appropriately. Risk of Hepatitis, Hepatic Events: Monitor liver function tests prior to and during treatment. Risk of Withdrawal in Patients Dependent on Full Agonist Opioids: Verify that patient is clinically stable on transmucosal buprenorphine before injecting SUBLOCADE. Treatment of Emergent Acute Pain: Treat pain with a non-opioid analgesic whenever possible. If opioid therapy is required, monitor patients closely because higher doses may be required for analgesic effect. ADVERSE REACTIONS Adverse reactions commonly associated with SUBLOCADE (in ≥5% of subjects) were constipation, headache, nausea, injection site pruritus, vomiting, increased hepatic enzymes, fatigue, and injection site pain. For more information about SUBLOCADE, the full Prescribing information including BOXED WARNING, and Medication Guide, visit . About Opioid Use Disorder (OUD) Opioid Use Disorder (OUD) is a chronic disease in which people develop a pattern of using opioids that can lead to negative consequences.1 OUD may affect the parts of the brain that are necessary for life-sustaining functions.1,2 Important Cautionary Note Regarding Forward-Looking Statements This news release contains certain statements that are forward-looking. Forward-looking statements include, among other things, express and implied statements regarding: whether the FDA will approve the PAS which would allow us to update our label; the safety and efficacy of the new rapid induction protocol and alternative injection sites; enhanced patient experience, and expanded patient access and other statements containing the words "believe," "anticipate," "plan," "expect," "intend," "estimate," "forecast," "strategy," "target," "guidance," "outlook," "potential," "project," "priority," "may," "will," "should," "would," "could," "can," "outlook," "guidance," the negatives thereof, and variations thereon and similar expressions. By their nature, forward-looking statements involve risks and uncertainties as they relate to events or circumstances that may or may not occur in the future. Actual results may differ materially from those because they relate to future events. Various factors may cause differences between Indivior's expectations and actual results, including, among others, the fact that the regulatory approval process is uncertain and may prevent us from obtaining approvals for some or all of our product candidate; the FDA or other regulatory agencies may not agree with our regulatory approval strategies or components of our filings for our products and may not approve, or may delay the approval of, our products; and the risks described in our most recent annual report on Form 20-F beginning on page 9 as filed with the U.S. SEC and in subsequent releases. Forward-looking statements speak only as of the date that they are made and should be regarded solely as our current plans, estimates and beliefs. Except as required by law, we do not undertake and specifically decline any obligation to update, republish or revise forward-looking statements to reflect future events or circumstances or to reflect the occurrences of unanticipated events. About Indivior Indivior is a global pharmaceutical company working to help change patients' lives by developing medicines to treat substance use disorders (SUD), overdose and serious mental illnesses. Our vision is that all patients around the world will have access to evidence-based treatment for the chronic conditions and co-occurring disorders of SUD. Indivior is dedicated to transforming SUD from a global human crisis to a recognized and treated chronic disease. Building on its global portfolio of OUD treatments, Indivior has a pipeline of product candidates designed to both expand on its heritage in this category and potentially address other chronic conditions and co-occurring disorders of SUD. Headquartered in the United States in Richmond, VA, Indivior employs over 1,000 individuals globally and its portfolio of products is available in over 30 countries worldwide. Visit to learn more. Connect with Indivior on LinkedIn by visiting . References National Academies of Sciences, Engineering, and Medicine; Health and Medicine Division; Board on Health Sciences Policy; Committee on Medication-Assisted Treatment for Opioid Use Disorder, Mancher, M., & Leshner, A. I. (Eds.). (2019). Medications for Opioid Use Disorder Save Lives. National Academies Press (US). Accessed October 30, 2023, from NIDA. 2022, March 22. Drugs and the Brain. Accessed October 30,2023, from SOURCE Indivior PLC WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED