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A Feasibility Study for a Novel Trans-infraorbital Canal Approach to the Maxillary Nerve in Pigs (Sus domesticus). 猪上颌神经经眶窦入路的可行性研究
Pub Date : 2024-04-01 Epub Date: 2024-02-20 DOI: 10.30802/AALAS-CM-23-000045
Stephanie A Hon, Stephen Parry, Jordyn M Boesch, Cristina de Miguel Garcia

Experimental maxillofacial surgery is commonly performed in pigs; however, locoregional anesthesia of this area has not been described. This study evaluated the feasibility of a novel maxillary nerve block approach. In part I, cadavers were used to determine anatomic landmarks and assess maxillary nerve dye staining by using 0.03 mL kg-1 of a 1:10 mixture of commercial food dye and 0.5% bupivacaine. In part II, 10 additional pig cadavers underwent bilateral ultrasound-guided maxillary nerve blocks by using trans-infraorbital canal needle placement. The maxillary nerve was harvested and scored based on degree of staining (0 and 1, absent or incomplete staining; 2, staining; >1 cm circumferentially). Intracranial and intraconal spread of dye was evaluated. A Kruskal-Wallis test was used to compare infraorbital canal length estimated either externally via landmarks, internally via ultrasound, or actually measured after dissection. In 18 of 20 (90%) injections, successful staining (score = 2) of maxillary nerves was obtained for a nerve length of 2.4 ± 0.3 cm. Two of 20 cases (10%) had inadequate staining (score <2). At dissection of these 2 cases, the needle tip was observed to have collided with an unerupted tooth (third molar). No intracranial or intraconal spread of dye was observed. We detected no statistical differences between the estimated external, estimated internal, or actual dissection methods for measurement of infraorbital canal length (P = 0.3). Ultrasound-guided trans-infraorbital maxillary nerve block in pigs is a feasible technique, warranting further work to evaluate its in vivo efficacy and safety.

实验性颌面外科手术通常是在猪身上进行的;然而,对这一区域进行局部麻醉的情况尚未见报道。本研究评估了新型上颌神经阻滞方法的可行性。在第一部分中,使用 0.03 mL kg-1 的商用食用染料和 0.5% 布比卡因的 1:10 混合物,用尸体确定解剖标志并评估上颌神经染色。在第二部分中,又有 10 头猪尸体在超声波引导下进行了双侧上颌神经阻滞,采用的是经眶下管置入针的方法。采集上颌神经并根据染色程度进行评分(0 和 1,无染色或染色不完全;2,染色;周长大于 1 厘米)。对染色剂在颅内和结节内的扩散情况进行评估。采用 Kruskal-Wallis 检验比较眶下管长度,比较方法包括通过地标进行外部估计、通过超声波进行内部估计或解剖后实际测量。在 20 次注射中,有 18 次(90%)上颌神经染色成功(得分 = 2),神经长度为 2.4 ± 0.3 厘米。20 例中有 2 例(10%)染色不充分(得分 P = 0.3)。超声引导下经猪眶内上颌神经阻滞是一种可行的技术,值得进一步研究以评估其在体内的有效性和安全性。
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引用次数: 0
Methods for Decreasing Preweaning Mortality in a Fragile Mouse Model of Hypomorphic Collagen VII Deficiency. 降低畸形胶原蛋白 VII 缺乏症脆性小鼠模型断奶前死亡率的方法。
Pub Date : 2024-04-01 Epub Date: 2024-03-20 DOI: 10.30802/AALAS-CM-23-000087
Chloe L Strege, William C Miller, Cindy Eide, Jennifer Hubbard, Jakub Tolar

Preweaning mortality is a widespread problem in laboratory mouse breeding, particularly in the case of fragile mouse models. While numerous studies explore alternative care methods to increase the survivability of common mouse strains, there remains a paucity of research into the care of mice with fragile health conditions that result from induced or natural genetic mutations. In this study, standard husbandry practices were enhanced by the addition of a softened diet, a nutritionally fortified dietary supplement, soft bedding, gentle handling techniques, decreased handling, lengthened weaning age, and dam productivity tracking. This alternative care plan was shown to increase the survival of a fragile recessive dystrophic epidermolysis bullosa mouse model, and some aspects could be used in developing a care plan for other fragile mouse strains.

断奶前死亡是实验室小鼠育种中的一个普遍问题,尤其是脆弱小鼠模型。尽管许多研究都在探索替代饲养方法以提高普通小鼠品系的存活率,但对于如何饲养因诱导或自然基因突变而导致健康状况脆弱的小鼠的研究仍然很少。在这项研究中,标准饲养方法通过添加软化饲料、营养强化食品、柔软的垫料、轻柔的操作技术、减少操作、延长断奶年龄和跟踪母鼠生产率得到了加强。结果表明,这种替代饲养计划提高了脆性隐性营养不良性表皮松解症小鼠模型的存活率,其中某些方面可用于为其他脆性小鼠品系制定饲养计划。
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引用次数: 0
Abnormal Feather Phenotype Associated with a Fatal Stress Response and Unusual Tolerance to Human Contact in the Zebra Finch (Taeniopygia castanotis). 斑马雀(Taeniopygia castanotis)的异常羽毛表型与致命的应激反应和对人类接触的异常耐受性有关。
Pub Date : 2024-04-01 Epub Date: 2024-03-20 DOI: 10.30802/AALAS-CM-23-000064
Lucas R West, Lainy B Day

The zebra finch (Taeniopygia castanotis) is a songbird sold in the pet trade and commonly used in research. In this report, we describe a set of partially overlapping traits shared by 3 birds in 2 broods from the same nest box that included atypical morphologic, developmental, and behavioral characteristics. The most obvious feature of this novel phenotype was feathers exhibiting a clumped appearance, which was accompanied by slow growth, delayed expression of adult plumage traits, and tameness, which we define as a lack of escape response upon handling without behavioral indicators of stress such as rapid breathing. Surprisingly, these birds also displayed a fatal response to nonhuman stressors. In one brood, a male expressed all of these characteristics, 2 females were wild-type, and a male sibling expressed only a hyperactive stress response but was otherwise normal. This indicates that the stress response could be inherited independently of the other abnormalities found in the male nest mate. In a second brood, a male bearing the abnormal feather phenotype behaved similarly to the male in the first brood, supporting the possibility that tameness is genetically associated with the unusual feather phenotype. The 2 other male and 2 female nest mates from this brood were behaviorally and visually normal, although the females developed slowly. Although similar traits have appeared in the aviary previously, such as slow development and small size, these are the first cases documented in detail. This correlated suite of traits suggests a linkage among altered feather growth, developmental rate, and brain and/or physiologic traits influencing normal fear and stress responses in the zebra finch. Awareness and study of the mechanism(s) linking these traits by examination of underlying genetic or environmental factors will allow a better understanding of the relationship between physical and behavioral traits in domesticated laboratory animals.

斑马雀(Taeniopygia castanotis)是一种在宠物市场上出售的鸣禽,通常用于研究。在本报告中,我们描述了来自同一巢箱的两窝 3 只斑马雀所共有的一系列部分重叠的特征,包括非典型的形态、发育和行为特征。这种新表型最明显的特征是羽毛呈团块状,同时还伴有生长缓慢、成羽性状表达延迟和温顺。令人惊讶的是,这些鸟对非人类压力也表现出致命的反应。在一窝雏鸟中,一只雄鸟表现出了所有这些特征,两只雌鸟是野生型的,一只雄鸟兄弟姐妹只表现出了过度活跃的应激反应,但其他方面都很正常。这表明,应激反应的遗传可能与雄性巢伴的其他异常情况无关。在第二窝中,一只具有异常羽毛表型的雄性与第一窝中的雄性表现相似,这支持了驯化与异常羽毛表型遗传相关的可能性。这窝雏鸟中的另外两只雄鸟和两只雌鸟的行为和视觉均正常,但雌鸟发育缓慢。虽然鸟舍中以前也出现过类似的特征,如发育缓慢和体型较小,但这些是首次详细记录的案例。这一系列相关的性状表明,斑马雀的羽毛生长、发育速度、大脑和/或生理特征的改变与正常的恐惧和应激反应之间存在联系。通过研究潜在的遗传或环境因素来认识和研究这些性状之间的关联机制,将有助于更好地理解驯化实验动物的身体和行为性状之间的关系。
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引用次数: 0
Comparison of Two Different Alfaxalone Concentrations Combined with Midazolam to Anesthetize Cynomolgus Macaques (Macaca fascicularis) for Plethysmography. 比较两种不同浓度的阿法沙酮与咪达唑仑联合使用来麻醉猕猴(Macaca fascicularis)以进行褶皱测量。
Pub Date : 2024-04-01 Epub Date: 2024-03-21 DOI: 10.30802/AALAS-CM-23-000069
Robert J Edwards, Jeanean M Ghering, Ondraya M Frick, Kirby S Pasloske, Kacee H Santos, Summer M Astleford, Charles E White, Brianna M Marion

Plethysmography is employed in nonhuman primates (NHPs) to calculate respiratory minute volume and determine the exposure time required to deliver an aerosol at the target dose. Anesthetic drugs can impact breathing parameters like steady-state minute volume (SSMV) central to aerosol dosing. Alfaxalone-midazolam mixtures (AM) provide superior parameters for plethysmography in cynomolgus macaques. An obstacle to the use of AM is the volume required to anesthetize via intramuscular injection. A more concentrated formulation of alfaxalone will reduce injection volumes and refine AM protocols. The purpose of this study was to compare AM using the Indexed 10-mg/mL (AM10) formulation compared with an investigational 40-mg/mL (AM40) formulation for IM administration in cynomolgus macaques undergoing plethysmography. We hypothesized that AM10 and AM40 would show no difference in quality of anesthesia (QA), duration of anesthesia, SSMV, accumulated minute volume (AMV), and side effects. We also hypothesized that female macaques would have a longer duration of anesthesia compared with males using both formulations. The study used 15 cynomolgus macaques comprised of 8 females and 7 males. NHPs were compared between 2 separate and randomized anesthetic events no less than one week apart. Each animal served as its own control and animals were randomized by random number generation. Anesthetized NHPs were placed in a sealed plethysmography chamber, and minute volume measurements were calculated every 10 s to determine SSMV. Once SSMV was achieved for 20 min, the trial ended. There were no statistically significant differences between AM10 and AM40 for duration of anesthesia, SSMV, AMV, side effects, or QA. AM40 had a significantly smaller injection volume. Females did not show a significantly longer median duration of anesthesia using either of the alfaxalone formulations. Overall, AM40 offers a more humane anesthetic than AM10 for plethysmography in cynomolgus macaques.

在非人灵长类动物(NHPs)中使用胸廓测量法来计算呼吸分量,并确定按目标剂量投放气雾剂所需的暴露时间。麻醉药物会影响呼吸参数,如对气雾剂剂量至关重要的稳态分钟量(SSMV)。阿法沙龙-咪达唑仑混合物(AM)为犬猕猴的胸透提供了出色的参数。使用阿法沙酮的一个障碍是通过肌肉注射进行麻醉所需的剂量。一种浓度更高的阿法沙酮制剂将减少注射量并改进 AM 方案。本研究的目的是比较使用指数化 10 毫克/毫升(AM10)制剂和研究性 40 毫克/毫升(AM40)制剂进行肌肉注射的猕猴在接受胸透检查时的麻醉效果。我们假设 AM10 和 AM40 在麻醉质量 (QA)、麻醉持续时间、SSMV、累积分钟量 (AMV) 和副作用方面没有差异。我们还假设,与使用这两种配方的雄性猕猴相比,雌性猕猴的麻醉持续时间更长。这项研究使用了 15 只猕猴,其中 8 只为雌性,7 只为雄性。在间隔不少于一周的两次独立和随机麻醉事件中对 NHP 进行了比较。每只动物都作为自己的对照组,并通过随机数生成对动物进行随机分组。将麻醉后的 NHP 放入密封的胸透室中,每隔 10 秒计算一次分钟体积,以确定 SSMV。20 分钟达到 SSMV 后,试验结束。在麻醉持续时间、SSMV、AMV、副作用或质量保证方面,AM10 和 AM40 之间没有明显的统计学差异。AM40 的注射量明显较小。女性使用两种阿伐沙龙制剂的中位麻醉持续时间都没有明显延长。总体而言,AM40 比 AM10 对绒毛膜促性腺激素猕猴的麻醉更人道。
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引用次数: 0
Chlamydia muridarum Associated Pulmonary and Urogenital Disease and Pathology in a Colony of Enzootically Infected Il12rb2 Deficient and Stat1 Knockout Mice. Il12rb2缺失和Stat1基因敲除小鼠群落中与鼠衣原体相关的肺部和泌尿系统疾病及病理变化
Pub Date : 2024-04-01 DOI: 10.30802/AALAS-CM-24-000002
Noah Mishkin, Ileana C Miranda, Sebastian E Carrasco, Christopher Cheleuitte-Nieves, Rodolfo Ricart J Arbona, Claire Wingert, Joseph C Sun, Neil S Lipman

Chlamydia muridarum (Cm), an intracellular bacterium of historical importance, was recently rediscovered as moderately prevalent in research mouse colonies. Cm was first reported as a causative agent of severe pneumonia in mice about 80 y ago, and while it has been used experimentally to model Chlamydia trachomatis infection of humans, there have been no further reports of clinical disease associated with natural infection. We observed clinical disease and pathology in 2 genetically engi- neered mouse (GEM) strains, Il12rb2 KO and STAT1 KO, with impaired interferon-γ signaling and Th1 CD4+ T cell responses in a colony of various GEM strains known to be colonized with and shedding Cm. Clinical signs included poor condition, hunched posture, and poor fecundity. Histopathology revealed disseminated Cm with lesions in pulmonary, gastrointestinal, and urogenital tissues. The presence of Cm was confirmed using both immunohistochemistry for Cm major outer membrane protein-1 antigen and in situ hybridization using a target probe directed against select regions of Cm strain Nigg. Cm was also found in association with a urothelial papilloma in one mouse. These cases provide additional support for excluding Cm from research mouse colonies.

鼠衣原体(Chlamydia muridarum,Cm)是一种具有重要历史意义的细胞内细菌,最近再次被发现在研究小鼠群中中度流行。大约 80 年前,Cm 首次被报道为小鼠重症肺炎的致病菌,虽然它已被用于沙眼衣原体感染人类的实验模型,但还没有与自然感染相关的临床疾病的进一步报道。我们观察了两个基因工程小鼠(GEM)品系(Il12rb2KO 和 STAT1KO)的临床疾病和病理变化,它们在已知有沙眼衣原体定植和脱落的各种 GEM 品系群中的干扰素-γ 信号传导和 Th1 CD4+ T 细胞反应受损。临床症状包括体质差、姿势驼背和繁殖力低下。组织病理学显示,Cm呈播散性,在肺部、胃肠道和泌尿生殖系统组织中均有病变。用免疫组化法检测 Cm 主要外膜蛋白-1 抗原,并用针对 Cm 株 Nigg 选择区域的靶探针进行原位杂交,证实了 Cm 的存在。在一只小鼠的尿道乳头状瘤中也发现了 Cm。这些病例为将 Cm 排除在研究小鼠群落之外提供了更多支持。
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引用次数: 0
Assessment of the Inflammatory Effects of Gut Microbiota from Human Twins Discordant for Ulcerative Colitis on Germ-free Mice. 评估溃疡性结肠炎不一致人类双胞胎肠道微生物群对无菌小鼠炎症的影响
Pub Date : 2024-04-01 Epub Date: 2024-03-20 DOI: 10.30802/AALAS-CM-23-000065
Lina A Knudsen, Line Sf Zachariassen, Mikael L Strube, Jesper F Havelund, Bartosz Pilecki, Anders B Nexoe, Frederik T Møller, Signe B Sørensen, Niels Marcussen, Nils J Faergeman, Andre Franke, Corinna Bang, Uffe Holmskov, Axel K Hansen, Vibeke Andersen

Disturbances in gut microbiota are prevalent in inflammatory bowel disease (IBD), which includes ulcerative colitis (UC). However, whether these disturbances contribute to development of the disease or are a result of the disease is unclear. In pairs of human twins discordant for IBD, the healthy twin has a higher risk of developing IBD and a gut microbiota that is more similar to that of IBD patients as compared with healthy individuals. Furthermore, appropriate medical treatment may mitigate these disturbances. To study the correlation between microbiota and IBD, we transferred stool samples from a discordant human twin pair: one twin being healthy and the other receiving treatment for UC. The stool samples were transferred from the disease-discordant twins to germ-free pregnant dams. Colitis was induced in the offspring using dextran sodium sulfate. As compared with offspring born to mice dams inoculated with stool from the healthy cotwin, offspring born to dams inoculated with stool from the UC-afflicted twin had a lower disease activity index, less gut inflammation, and a microbiota characterized by higher α diversity and a more antiinflammatory profile that included the presence and higher abundance of antiinflammatory species such as Akkermansia spp., Bacteroides spp., and Parabacteroides spp. These findings suggest that the microbiota from the healthy twin may have had greater inflammatory properties than did that of the twin undergoing UC treatment.

肠道微生物群紊乱在炎症性肠病(IBD)(包括溃疡性结肠炎(UC))中十分普遍。然而,这些紊乱是导致疾病发展还是疾病的结果尚不清楚。在一对IBD不一致的人类双胞胎中,健康的双胞胎患IBD的风险较高,与健康人相比,肠道微生物群与IBD患者更为相似。此外,适当的药物治疗可减轻这些紊乱。为了研究微生物群与 IBD 之间的相关性,我们转移了一对不和谐人类双胞胎的粪便样本:其中一对双胞胎是健康的,另一对正在接受 UC 治疗。我们将这对不和双胞胎的粪便样本转移到无菌的怀孕母体中。使用葡聚糖硫酸钠诱导后代患上结肠炎。与接种了健康同卵双胞胎粪便的母鼠所生的后代相比,接种了患有 UC 的双胞胎粪便的母鼠所生的后代疾病活动指数较低,肠道炎症较轻,微生物群的α多样性较高,抗炎性较强,包括抗炎物种(如 Akkermansia spp、这些发现表明,与接受 UC 治疗的双胞胎相比,健康双胞胎的微生物群可能具有更强的抗炎特性。
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引用次数: 0
Pigs in Transplantation Research and Their Potential as Sources of Organs in Clinical Xenotransplantation. 移植研究中的猪及其作为临床异种移植器官来源的潜力。
Pub Date : 2024-04-01 Epub Date: 2024-02-15 DOI: 10.30802/AALAS-CM-23-000030
S Sikandar Raza, Hidetaka Hara, Willard Eyestone, David Ayares, David C Cleveland, David K C Cooper

The pig has long been used as a research animal and has now gained importance as a potential source of organs for clinical xenotransplantation. When an organ from a wild-type (i. e., genetically unmodified) pig is transplanted into an immunosuppressed nonhuman primate, a vigorous host immune response causes hyperacute rejection (within minutes or hours). This response has been largely overcome by 1) extensive gene editing of the organ-source pig and 2) the administration to the recipient of novel immunosuppressive therapy based on blockade of the CD40/CD154 T cell costimulation pathway. Gene editing has consisted of 1) deletion of expression of the 3 known carbohydrate xenoantigens against which humans have natural (preformed) antibodies and 2) the introduction of human 'protective' genes. The combination of gene editing and novel immunosuppressive therapy has extended life-supporting pig kidney graft survival to greater than 1 y and of pig heart survival to up to 9 mo. This review briefly describes the techniques of gene editing, the potential risks of transfer of porcine endogenous retroviruses with the organ, and the need for breeding and housing of donor pigs under biosecure conditions.

长期以来,猪一直被用作研究动物,现在作为临床异种移植的潜在器官来源,其重要性日益凸显。当来自野生型猪(即基因未修改的猪)的器官移植到免疫抑制的非人灵长类动物体内时,强烈的宿主免疫反应会导致超急性排斥反应(数分钟或数小时内)。这种反应在很大程度上是通过以下方法克服的:1)对器官来源猪进行广泛的基因编辑;2)向受体施用基于阻断 CD40/CD154 T 细胞成本刺激途径的新型免疫抑制疗法。基因编辑包括:1)删除人类具有天然(预形成)抗体的 3 种已知碳水化合物异抗原的表达;2)引入人类 "保护 "基因。基因编辑与新型免疫抑制疗法相结合,已将维持生命的猪肾脏移植存活期延长至 1 年以上,猪心脏存活期延长至 9 个月。 本综述简要介绍了基因编辑技术、猪内源性逆转录病毒随器官转移的潜在风险,以及在生物安全条件下繁殖和饲养供体猪的必要性。
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引用次数: 0
Perioperative Evaluation of Arterial and Venous Whole Blood in the Lamb (Ovis aries) Fontan Model. 羔羊(Ovis aries)Fontan 模型中动脉和静脉全血的围手术期评估。
Pub Date : 2024-04-01 Epub Date: 2024-03-20 DOI: 10.30802/AALAS-CM-24-000008
William E Schwartzman, Jingru Che, Mark A Naguib, Jack Palillo, Michael Jimenez, Mackenzie E Turner, Andrew R Yates, Carmen Arsuaga-Zorrilla, Christopher Breuer, John Kelly

Whole blood analysis can evaluate numerous parameters, including pH, pCO₂, pO₂, HCO₃ - , base excess, glucose, electrolytes, lactate, blood urea nitrogen, creatinine, bilirubin, and hemoglobin. This valuable tool enables clinicians to make more informed decisions about patient care. However, the current body of literature describing perioperative whole blood analysis in Dorset sheep (Ovis aries) is small, so clinicians lack adequate information to guide their decision-making when evaluating test results. We evaluated arterial and venous whole blood pH, bicarbonate, pCO₂, lactate, creatinine, and blood urea nitrogen before and for the first 24 hours after surgery in 2 cohorts of male and female Ovis arie s undergoing one of 2 major cardiovascular procedures, a Single-Stage Fontan or an inferior vena cava to pulmonary artery extracardiac conduit implantation (IP-ECC). The cohort undergoing a Single-Stage Fontan, which is the more complex procedure, exhibited greater deviation from baseline measurements than did the cohort undergoing the IP-ECC for lactate, bicarbonate, and creatinine. The cohort undergoing the IP-ECC showed no significant deviation from baseline for any parameters, potentially indicating a better safety margin than expected when compared with the Single-Stage Fontan. Together, these results indicate the clinical value of arterial and venous whole blood measurements in perioperative management of sheep and can provide a reference for clinicians managing sheep after significant cardiovascular procedures.

全血分析可评估多种参数,包括 pH 值、pCO₂、pO₂、HCO₃-、碱过量、葡萄糖、电解质、乳酸盐、血尿素氮、肌酐、胆红素和血红蛋白。这一宝贵的工具使临床医生能够就患者护理做出更明智的决定。然而,目前描述多塞特绵羊(Ovis aries)围手术期全血分析的文献很少,因此临床医生在评估检测结果时缺乏足够的信息来指导决策。我们对接受单级方坦或下腔静脉至肺动脉心外导管植入术(IP-ECC)这两种主要心血管手术之一的两组雌雄多塞特绵羊在手术前和手术后 24 小时内的动脉和静脉全血 pH 值、碳酸氢盐、pCO₂、乳酸盐、肌酐和血尿素氮进行了评估。接受单级方坦手术的人群比接受IP-ECC手术的人群的乳酸、碳酸氢盐和肌酐测量值偏离基线的程度更大。而接受IP-ECC手术的人群在任何参数上都没有明显偏离基线,这可能表明与单级方坦手术相比,IP-ECC手术的安全系数比预期的要高。总之,这些结果表明了动脉和静脉全血测量在绵羊围手术期管理中的临床价值,可为临床医生管理重大心血管手术后的绵羊提供参考。
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引用次数: 0
Carprofen Attenuates Postoperative Mechanical and Thermal Hypersensitivity after Plantar Incision in Immunodeficient NSG Mice. 卡泊芬能减轻免疫缺陷 NSG 小鼠足底切口术后的机械和热超敏反应。
Pub Date : 2024-04-01 Epub Date: 2024-03-29 DOI: 10.30802/AALAS-CM-23-000058
Eden D Alamaw, Kerriann M Casey, Krystal Tien, Benjamin D Franco, Gregory Gorman, Renee M Cotton, Claude Nagamine, Katechan Jampachaisri, Patrick Sharp, Cholawat Pacharinsak, Monika K Huss

Immunodeficient NSG mice are reported to be less responsive to buprenorphine analgesia. Here, we used NSG mice to compare the efficacy of the commonly used dose of carprofen (5 mg/kg) with 5 and 10 times that dose (25 and 50 mg/kg) for attenuating postoperative mechanical and thermal hypersensitivity following an incisional pain model. Male and female NSG mice (n = 45) were randomly assigned to one of 4 groups and received daily subcutaneous injections for 3 d: saline (5 mL/kg), 5 mg/kg carprofen (Carp5), 25 mg/kg carprofen (Carp25), and 50 mg/kg carprofen (Carp50). Mechanical and thermal hypersensitivity were assessed 24 h before and at 4, 24, and 48 h after surgery. Plasma carprofen concentrations were measured in a separate group of mice (n = 56) on days 0 (at 2, 4, 12, and 23 h), 1, and 2 after the first, second, and third doses, respectively. Toxicity was assessed through daily fecal occult blood testing (n = 27) as well as gross and histopathologic evaluation (n = 15). Our results indicated that the saline group showed both mechanical and thermal hypersensitivity throughout the study. Carp5 did not attenuate mechanical or thermal hypersensitivity at any time point. Carp25 attenuated mechanical and thermal (except for the 4-h time point) hypersensitivity. Carp50 attenuated only thermal hypersensitivity at 24 h. Fecal occult blood was detected in 1 of 8 Carp25-treated mice at 48 and 72 h. Histopathologic abnormalities (gastric ulceration, ulcerative enteritis, and renal lesions) were observed in some Carp50-treated mice. Plasma carprofen concentrations were dose and time dependent. Our results indicate that Carp25 attenuated postoperative mechanical and thermal hypersensitivity more effectively than Carp5 or Carp50 in NSG mice with incisional pain. Therefore, we recommend providing carprofen at 25 mg/kg SID for incisional pain procedures using immunodeficient NSG mouse.

据报道,免疫缺陷NSG小鼠对丁丙诺啡镇痛的反应较弱。在此,我们使用 NSG 小鼠比较了常用剂量的卡泊芬净(5 毫克/千克)与 5 倍和 10 倍剂量的卡泊芬净(25 毫克/千克和 50 毫克/千克)对减轻切口疼痛模型术后机械和热超敏反应的疗效。雄性和雌性 NSG 小鼠(n = 45)被随机分配到 4 组中的一组,在 3 天内每天接受皮下注射:生理盐水(5 mL/kg)、5 mg/kg 卡洛芬(Carp5)、25 mg/kg 卡洛芬(Carp25)和 50 mg/kg 卡洛芬(Carp50)。在手术前 24 小时以及手术后 4、24 和 48 小时对机械和热过敏性进行评估。在第一、第二和第三剂量后的第 0 天(2、4、12 和 23 小时)、第 1 天和第 2 天,分别测量另一组小鼠(n = 56)的血浆卡洛芬浓度。毒性通过每日粪便隐血检测(n = 27)以及大体和组织病理学评估(n = 15)进行评估。我们的结果表明,生理盐水组在整个研究过程中都表现出机械和热过敏。鲤鱼 5 在任何时间点都不会减轻机械或热过敏反应。鲤鱼 25 可减轻机械和热过敏(4 小时时间点除外)。一些经 Carp50 处理的小鼠出现了组织病理学异常(胃溃疡、溃疡性肠炎和肾脏病变)。血浆中的卡洛芬浓度与剂量和时间有关。我们的研究结果表明,在切口疼痛的 NSG 小鼠中,Carp25 比 Carp5 或 Carp50 能更有效地减轻术后机械和热超敏反应。因此,我们建议在使用免疫缺陷的 NSG 小鼠进行切口疼痛手术时提供 25 mg/kg SID 的卡泊芬钠。
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引用次数: 0
Binding Affinity, Selectivity, and Pharmacokinetics of the Oxytocin Receptor Antagonist L-368,899 in the Coyote (Canis latrans). 土狼体内催产素受体拮抗剂 L-368,899 的结合亲和力、选择性和药代动力学。
Pub Date : 2024-02-01 DOI: 10.30802/AALAS-CM-23-000044
Sara M Freeman, J Leon Catrow, James Eric Cox, Alexandra Turano, McKenna A Rich, Hillary P Ihrig, Naveena Poudyal, Cheng-Wei Tom Chang, Eric M Gese, Julie K Young, Aaron L Olsen

L-368,899 is a selective small-molecule oxytocin receptor (OXTR) antagonist originally developed in the 1990s to prevent preterm labor. Although its utility for that purpose was limited, L-368,899 is now one of the most commonly used drugs in animal research for the selective blockade of neural OXTR after peripheral delivery. A growing number of rodent and primate studies have used L-368,899 to evaluate whether certain behaviors are oxytocin dependent. These studies have improved our understanding of oxytocin's function in the brains of rodents and monkeys, but very little work has been done in other mammals, and only a single paper in macaques has provided any evidence that L-368,899 can be detected in the CNS after peripheral delivery. The current study sought to extend those findings in a novel species: coyotes ( Canis latrans ). Coyotes are ubiquitous North American canids that form long-term monogamous pair-bonds. Although monogamy is rare in rodents and primates, all wild canid species studied to date exhibit social monogamy. Coyotes are therefore an excellent model organism for the study of oxytocin and social bonds. Our goal was to determine whether L-368,899 is a viable candidate for future use in behavioral studies in coyotes. We used captive coyotes at the USDA National Wildlife Research Center's Predator Research Facility to evaluate the pharmacokinetics of L-368,899 in blood and CSF during a 90-min time course after intramuscular injection. We then characterized the binding affinity and selectivity of L-368,899 to coyote OXTR and the structurally similar vasopressin 1a receptor. We found that L-368,899 peaked in CSF at 15 to 30 min after intramuscular injection and slowly accumulated in blood. L-368,899 was 40 times more selective for OXTR than vasopressin 1a receptors and bound to the coyote OXTR with an affinity of 12 nM. These features of L-368,899 support its utility in future studies to probe the oxytocin system of coyotes.

L-368,899 是一种选择性小分子催产素受体(OXTR)拮抗剂,最初开发于 20 世纪 90 年代,用于预防早产。尽管其用途有限,但 L-368,899 现在已成为动物研究中最常用的药物之一,用于在外周分娩后选择性阻断神经催产素受体。越来越多的啮齿类动物和灵长类动物研究使用 L-368,899 来评估某些行为是否依赖催产素。这些研究增进了我们对催产素在啮齿类动物和猴子大脑中功能的了解,但对其他哺乳动物的研究却很少,只有一篇关于猕猴的论文提供了任何证据,证明 L-368,899 可以在外周给药后在中枢神经系统中被检测到。目前的研究试图在一种新物种--郊狼(Canis latrans)身上扩展这些发现。郊狼是北美无处不在的犬科动物,它们会形成长期的一夫一妻制配对关系。虽然一夫一妻制在啮齿类动物和灵长类动物中很少见,但迄今为止研究的所有野生犬科动物都表现出社会一夫一妻制。因此,郊狼是研究催产素和社会纽带的极佳模式生物。我们的目标是确定 L-368,899 是否是将来用于郊狼行为研究的可行候选物质。我们利用美国农业部国家野生动物研究中心捕食者研究机构的圈养土狼,评估了 L-368,899 肌肉注射后 90 分钟内血液和脑脊液中的药代动力学。然后,我们鉴定了 L-368,899 与郊狼 OXTR 和结构相似的加压素 1a 受体的结合亲和力和选择性。我们发现,肌肉注射后 15 至 30 分钟,L-368,899 在脑脊液中达到峰值,并在血液中缓慢累积。L-368,899 对 OXTR 的选择性是血管加压素 1a 受体的 40 倍,与土狼 OXTR 的结合亲和力为 12 nM。L-368,899的这些特点支持其在未来探究郊狼催产素系统的研究中发挥作用。
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引用次数: 0
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Comparative medicine
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