兽研类型：原创研究 发布日期：2026年10月5日 DOI：10.3389/fvets.2026.1954078 开放获取 编辑：Luca Pennasilico，意大利卡梅里诺大学 审稿：Jane Quandt，美国佐治亚大学；Stefanos G. Georgiou，希腊色萨利大学 *通讯作者：Won-Gyun Son carpeego@snu.ac.kr 收稿日期：2026年7月31日 修回日期：2026年9月7日 接受日期：2026年9月11日 发布日期：2026年10月5日 引用格式：Lee S, Oh S, Lee I and Son W-G (2026) Perioperative analgesic effects of opiranserin in canine castration: a pilot study. Front. Vet. Sci. 13:1954078. doi: 10.3389/fvets.2026.1954078 版权：©2026 Lee、Oh、Lee 与 Son。本文为开放获取文章，依据知识共享署名许可（CC BY）发布。在适当署名原作者及版权所有者、并引用本刊原始出版物、符合公认学术规范的前提下，允许在其他论坛使用、分发和复制本文。不得以违反上述条款的方式使用、分发或复制本文。 奥匹兰色林在犬去势术中的围手术期镇痛效果：一项初步研究 Seongwon Lee、Seonbin Oh、Inhyung Lee 与 Won-Gyun Son * 韩国首尔国立大学兽医学院兽医临床科学系 引言：奥匹兰色林是一种非阿片类镇痛药，作为甘氨酸转运体2抑制剂和5-HT2A受体拮抗剂发挥作用；本研究评估其在异氟烷麻醉下接受去势术的犬中减少术中补救镇痛需求及术后疼痛的效果。 材料与方法：将8只健康雄性比格犬随机分为两组，分别接受奥匹兰色林持续速率输注（诱导前1 h以5 mg·kg⁻¹·h⁻¹输注，随后以0.33 mg·kg⁻¹·h⁻¹输注9 h；n=4）或0.9%生理盐水（n=4）。使用阿法沙酮诱导麻醉，异氟烷（呼气末浓度1.5%）维持麻醉；所有犬术前均给予美洛昔康和头孢唑林，未实施局部区域镇痛。记录11个手术事件中的血流动力学反应（ΔMAP、ΔHR）；当两者均较基线升高≥20%时给予瑞芬太尼补救镇痛。拔管后30 min（T0）至T7采用格拉斯哥复合疼痛量表简表（GCMPS-SF）评估术后疼痛，评分≥5时给予补救镇痛。主要结局为术中补救镇痛频次和术后GCMPS-SF评分；次要结局为术中血流动力学反应、术后补救镇痛消耗量及不良反应。数据分析采用Mann–Whitney U检验和线性混合模型，并进行Bonferroni校正比较。 结果：奥匹兰色林组术中补救干预次数少于生理盐水组（中位数2 [2–2] 对 6.5 [3–9]；p=0.021）。GCMPS-SF评分显示分组效应（p=0.030）、时间效应（p=0.047）及分组×时间交互作用（p=0.034）显著，奥匹兰色林组在T1时评分较低（校正p=0.012），其他时间点无显著差异。次要结局中，ΔMAP（p=0.011）和ΔHR（p=0.048）存在显著的整体分组效应，两者均存在手术事件效应（p<0.001和p=0.008），但无分组×事件交互作用；校正后无单个事件存在显著差异。两组术后累积补救镇痛消耗量及不良反应发生率无差异。 结论：这些初步研究结果表明，奥匹兰色林可能减少犬的术中补救镇痛需求并减轻术后疼痛，值得在更大规模试验中加以证实。未观察到显著不良反应令人欣慰，但鉴于样本量较小，应谨慎解读。 关键词：奥匹兰色林、急性疼痛管理、5-HT2A拮抗剂、甘氨酸转运体2抑制剂、术中伤害感受、术后疼痛、犬去势术、补救镇痛 Frontiers in Veterinary Science 01 frontiersin.org
Lee 等，10.3389/fvets.2026.1954078 引言 有效的围手术期镇痛对兽医患者至关重要，因为疼痛控制不充分可增强交感神经和神经内分泌应激反应，并促进中枢敏化（1,2）。现行指南推荐使用阿片类药物、非甾体抗炎药（NSAIDs）和局部麻醉药作为犬猫急性手术疼痛的一线药物进行多模式镇痛（3）。其中，阿片类药物传统上被视为围手术期疼痛管理的基石，因其镇痛效果可靠且呈剂量依赖性（4）。尽管阿片类药物可提供强效镇痛，但其使用可能受到不良反应的限制，包括心动过缓、呼吸抑制、烦躁不安、呕吐、恶心和流涎（4）。这些局限性增加了人们对非阿片类镇痛药的兴趣，此类药物可减轻围手术期伤害感受，同时最大限度地减少阿片类药物相关不良反应。Opiranserin 是一种新型非阿片类镇痛药，可抑制甘氨酸转运体 2，从而增强脊髓甘氨酸能抑制，并拮抗 5-羟色胺 2A 受体，从而减弱下行 5-羟色胺能疼痛易化（5–7）。多项人体临床研究已考察了 opiranserin 的术后镇痛疗效（8,9）。在一项纳入 59 例接受腹腔镜胃切除术患者的 2 期试验中，与安慰剂相比，opiranserin 显著降低了术后疼痛强度，并使阿片类药物用量减少 29.5%（8）。在随后一项纳入 284 例接受腹腔镜结肠切除术患者的 3 期试验中，opiranserin 使患者自控镇痛需求减少 60.2%，阿片类药物用量减少 30.8%（9）。然而，在兽医学领域，仅有一项研究评估了其镇痛特性，该研究显示，与生理盐水（阴性对照）和低剂量瑞芬太尼（4 μg·kg −1 ·h −1 ，阳性对照）相比，六只比格犬的机械伤害感受阈值均升高，且在输注 60 至 240 分钟期间 opiranserin 超过瑞芬太尼（10）。因此，现有证据仍局限于人体术后临床试验和单一实验性兽医伤害感受模型；opiranserin 在实际临床手术环境中的围手术期镇痛疗效尚未得到评估。Opiranserin 的安全性数据也已有报道。在 1 期单次递增剂量研究中（单次 4 小时输注，最高 8 mg·kg −1 ），46 名健康志愿者中有 13 名（28.3%）发生药物相关不良事件，包括嗜睡、恶心、头晕和头痛；所有事件均为轻度和一过性，主要发生在最高剂量（6–8 mg·kg −1 ）时，并在停药后缓解（5）。在 2 期和 3 期试验中，opiranserin 组与安慰剂组的治疗中出现的不良事件发生率相当，被认为与药物相关的事件不常见且严重程度为轻至中度，无需干预即可缓解（8,9）。在任何试验中均未报告归因于 opiranserin 的严重不良事件。在比格犬中进行的唯一一项实验性研究中，opiranserin 的主要不良反应为 6 只犬中 2 只出现呕吐、6 只中 5 只出现类恶心体征；所有不良反应均在停止输注后 30 分钟内缓解，未观察到镇静、拟精神病样体征或神经系统体征（10）。综上所述，现有的疗效和安全性数据支持对 opiranserin 进行进一步评估，但二者均未在接受手术的犬中进行过评估。因此，本研究评估了 opiranserin 在接受去势手术的雄性犬中的围手术期镇痛疗效，去势是小动物临床实践中最常实施的择期手术之一（11）。选择该模型是因为其伤害感受事件易于检测，且其强度受术者影响极小，可提供标准化且可重复的手术刺激，预期术后疼痛为轻至中度，并具有明确的术中伤害感受事件，便于进行系统性血流动力学监测（12）。在此框架内，主要结局指标为术中补救镇痛频率和术后格拉斯哥复合疼痛量表简表（GCMPS-SF）评分，分别用于捕捉术中及术后阶段的镇痛疗效。次要结局指标为 11 项标准化手术事件期间平均动脉压（MAP）和心率（HR）的变化、术后补救镇痛药累积用量以及不良反应发生率。鉴于缺乏既往临床数据，本初步研究设计为探索性研究，旨在对 opiranserin 在临床手术环境中的围手术期镇痛效果生成初步估计。我们假设，与生理盐水相比，恒速输注（CRI）opiranserin 可减少术中补救镇痛需求、降低术后 GCMPS-SF 评分、减轻对手术刺激的血流动力学反应，并减少术后补救镇痛药用量。材料与方法 伦理批准 所有实验程序均经首尔国立大学机构动物护理和使用委员会批准（IACUC 编号 SNU-250728-4-2）。动物饲养和护理遵循《韩国实验动物法》的指南。动物与研究设计 八只健康、未去势的雄性比格犬被纳入这项随机、盲法、平行组对照初步研究。根据初步研究设计，每组分配四只犬：生理盐水（N/S）组（n=4）和 opiranserin 组（n=4）。所有犬均在全身麻醉下接受去势手术。分组采用随机数字表进行简单随机化，由不参与研究的独立第三方执行。在整个研究过程中，分组序列对术者、手术助手、麻醉师和疼痛评估者均设盲。所有手术均由同一名经验丰富的兽医外科医生完成，其在研究前已实施超过 50 例犬去势手术，采用标准化的《兽医科学前沿》02 frontiersin.org
Lee 等，10.3389/fvets.2026.1954078，采用在每个睾丸上方分别切开的开放式阴囊睾丸切除术。样本量：由于既往犬类外科研究未提供所选结局的效应量和变异性的可靠估计，因此未进行先验样本量计算。本研究为探索性预试验，纳入 8 只犬，每组分配 4 只，以在限制动物使用的同时获得治疗效应和变异性的初步估计。因此，结果被解释为初步性和产生假设性的。给药：奥匹兰色林用生理盐水稀释，于麻醉诱导前 1 小时开始以 CRI 方式给药，负荷剂量为 5 mg·kg⁻¹·h⁻¹，持续 1 小时，随后维持剂量为 0.33 mg·kg⁻¹·h⁻¹，持续 9 小时。N/S 组接受等体积、等速率的 0.9% 生理盐水。药物配制由一名对分组分配设盲的专职研究者完成。剂量选择与药代动力学依据：奥匹兰色林给药方案采用基于暴露的模型引导方法建立，参考了人体临床暴露数据和犬药代动力学模拟。在人体中，据报道与镇痛疗效相关的奥匹兰色林及其活性代谢物 VVZ-368 的合并血浆浓度约为 2,000–2,500 ng·ml⁻¹。由于全身至中枢神经系统暴露关系存在种属差异，且预期犬中枢神经系统暴露相对于全身血浆浓度更高，因此初始输注阶段选择了约 1,000–1,250 ng·ml⁻¹ 的较低暂定全身靶浓度。该值被视为务实的设计目标，而非经过验证的犬治疗浓度。该方案设计为两阶段输注，负荷阶段旨在手术刺激前快速达到药理学相关暴露，较低维持阶段旨在维持暴露的同时限制长时间全身蓄积。基于奥匹兰色林和 VVZ-368 合并暴露的蒙特卡洛药代动力学模拟（100 个虚拟受试者）支持先以 5 mg·kg⁻¹·h⁻¹ 输注 1 小时，随后以 0.33 mg·kg⁻¹·h⁻¹ 输注 9 小时，对应于 10 小时内总剂量约 8 mg·kg⁻¹。麻醉方案：使用阿法沙龙（2 mg·kg⁻¹ IV）诱导麻醉，并以固定呼气末浓度 1.5% 的异氟烷维持；所有犬在整个操作过程中均自主呼吸。该浓度保持恒定，以使对手术事件的血流动力学反应反映镇痛疗效差异，而非麻醉深度变化。通过下颌张力、眼睑反射、眼位和自主运动持续监测麻醉深度。若观察到麻醉深度不足的体征，则以 0.1% 的增量增加异氟烷。未给予阿片类药物术前用药或局部区域镇痛，以将奥匹兰色林的镇痛作用与其他药物的作用区分开来。所有犬均接受美洛昔康作为基线镇痛，并对任何符合预定标准的犬提供标准化的术中及术后补救镇痛。围手术期管理：诱导后立即给予美洛昔康（0.2 mg·kg⁻¹ IV）作为围手术期镇痛药（13），并在皮肤切开前 30 分钟给予头孢唑林（22 mg·kg⁻¹ IV）作为抗菌预防，符合研究当时实施的机构方案。液体治疗使用乳酸林格氏液，诱导前以 10 mL·kg⁻¹·h⁻¹ 输注 1 小时，然后从诱导至手术结束降至 5 mL·kg⁻¹·h⁻¹。方案规定了以下术中并发症干预措施：麻黄碱（0.05 mg·kg⁻¹ IV）用于低血压（MAP<60 mmHg）；格隆溴铵（5 μg·kg⁻¹ IV）用于伴低血压的心动过缓（HR<60 次/分并同时 MAP<60 mmHg）；以及对低体温（直肠温度<36.5°C）进行主动保温。整个麻醉期间通过直肠探头持续监测体温。术中伤害感受评估：通过置于右背侧跖动脉的动脉导管持续监测包括 MAP 和 HR 在内的血流动力学变量，并使用生命体征记录程序（Vital Recorder R）自动记录。手动记录 11 个标准化手术事件：E1，第一侧皮肤切开；E2，第一睾丸外置；E3，撕断第一睾丸附睾尾韧带；E4，钳夹第一睾丸精索；E5，切断第一睾丸精索；E6，第二侧皮肤切开；E7，第二睾丸外置；E8，撕断第二睾丸附睾尾韧带；E9，钳夹第二睾丸精索；E10，切断第二睾丸精索；E11，伤口闭合（14）。对于每个手术事件，将事件前 10 秒内记录的 MAP 和 HR 平均值指定为事件前基线。确定每个变量从事件时到下一事件开始时的最大值，并计算相对于基线的绝对变化（ΔMAP 和 ΔHR，分别以 mmHg 和次/分的绝对变化表示）。Frontiers in Veterinary Science 03 frontiersin.org
Lee等 10.3389/fvets.2026.1954078 术后疼痛及不良反应评估 术后疼痛采用GCMPS-SF进行评估，该工具是一种经过验证的多维疼痛评估工具，涵盖发声、对疼痛区域的关注、活动能力、对触摸的反应、神态以及姿势/活动（15）。所有评估均由一名经过培训且在整个研究过程中对分组分配不知情的单一研究者完成。由于评估期间犬只被单独饲养于标准笼具中，且中断研究中的CRI以允许活动会改变对研究治疗的暴露并混淆结果，因此省略了活动能力子量表，将最高可能评分从24分降至20分（15）。在拔管后30分钟（T0）以及从T1至T7每小时进行疼痛评估，共八次评估。T7后1小时内停止CRI，此后未再进行疼痛评估。所有犬只在T0时均完全清醒且能够自主活动，确认在开始疼痛评分前已充分从麻醉中恢复。本研究未对镇静进行正式评分。在整个术后观察期内记录不良反应的发生情况，包括呕吐、恶心和咂嘴（10）。对每只犬，记录作为术后补救镇痛给予的瑞芬太尼累积剂量（以μg·kg⁻¹表示），作为术后补救镇痛消耗量的衡量指标。补救镇痛 将MAP和HR均较事件前基线同时升高≥20%定义为给予术中补救镇痛的标准（16）。瑞芬太尼（0.5μg·kg⁻¹ IV）用作补救药物（17）。记录补救镇痛的时机和总次数。术后补救镇痛由瑞芬太尼以CRI（4μg·kg⁻¹·h⁻¹）给药1小时组成，在任何预定评估时间点GCMPS-SF评分达到≥5时启动（15,18）。若在随后的每小时评估中评分仍≥5，则CRI再维持一小时；若评分降至5以下，则停止CRI。选择瑞芬太尼作为术后补救药物是因为其超短的作用时间（3–10分钟）和快速消退，允许在每个每小时评估间隔内恢复至基线镇痛状态，从而最大限度地减少对后续GCMPS-SF评分的残留效应（19）。统计分析 主要结局——术中补救镇痛频率和术后GCMPS-SF疼痛评分——分析如下。术中补救镇痛频率采用Mann–Whitney U检验进行组间比较，并报告相应的Hodges–Lehmann中位数差异估计值及其95%置信区间作为效应量。术后GCMPS-SF评分采用线性混合模型（LMM）分析，以组别、时间（T0–T7）及其交互作用为固定效应，个体犬只为随机截距。固定效应通过最大似然估计拟合模型的似然比检验（χ²）进行评估。估计边际均值及各时间点组间对比来自限制性最大似然估计拟合的模型，自由度通过Kenward–Roger近似获得，p值在八个时间点间采用Bonferroni校正进行调整。次要结局——术中血流动力学反应、术后补救镇痛累积消耗量和不良反应发生率——分析如下。术中血流动力学数据采用LMM分析，以组别（N/S组 vs. 奥匹兰色林组）、手术事件（E1–E11）及其交互作用为固定效应，个体犬只为随机截距，使用限制性最大似然估计拟合；各手术事件的组间差异采用估计固定效应系数（β）及相应的t检验（df=6）评估，p值在11个手术事件间采用Bonferroni校正进行调整。术后补救镇痛累积消耗量和不良反应发生率采用Mann–Whitney U检验进行组间比较。p值<0.05被认为具有统计学显著性。在拟合每个LMM之前，使用Shapiro–Wilk检验评估残差的正态性，并通过残差图的目视检查评估方差齐性。根据似然比检验选择随机截距结构作为最简约模型。置信区间未针对多重比较进行调整，描述每个个体估计值的精确度，而p值在指示处跨比较采用Bonferroni校正；因此，排除零值的区间不一定对应于显著的校正后p值。鉴于探索性初步设计及所分析结局的多重性，所有统计学显著发现均应谨慎解读，因为在具有众多终点的把握度不足的研究中，I类错误的风险固有升高。结果 主要结局 平均手术时间为26.5±8.5分钟（范围18–40分钟）。奥匹兰色林组所需的术中补救镇痛干预次数显著少于N/S组[中位数2次（范围2–2；全部四只犬均在恰好两个事件时接受补救）vs. 6.5次（范围3–9）；Hodges–Lehmann中位数差异4.0次干预，95% CI 1.0–7.0；Mann–Whitney U检验，p=0.021]。在11个标准化手术事件中，奥匹兰色林组全部四只犬均分别在恰好两个事件时接受补救镇痛，尽管这些补救事件在个体犬只中发生于不同的手术步骤。相反，N/S组犬只接受补救镇痛三至九次，N/S组每只个体的补救次数均超过奥匹兰色林组任何犬只（图1）。值得注意的是，在E2（第一睾丸外置）——该手术模型中伤害性最强的事件——N/S组全部四只犬均需要至少一次 Frontiers in Veterinary Science 04 frontiersin.org
Lee 等 10.3389/fvets.2026.1954078 图1 各受试个体在整个手术事件中的术中补救镇痛频率。实心圆（•）和空心圆（◦）分别表示 N/S 组（n=4）和奥匹兰色林组（n=4）的补救事件。虚线将两组分开。E1，第一侧皮肤切开；E2，第一枚睾丸外置；E3，第一枚睾丸附睾尾韧带撕裂；E4，第一枚睾丸精索钳夹；E5，第一枚睾丸精索切断；E6，第二侧皮肤切开；E7，第二枚睾丸外置；E8，第二枚睾丸附睾尾韧带撕裂；E9，第二枚睾丸精索钳夹；E10，第二枚睾丸精索切断；E11，伤口闭合。补救干预，而奥匹兰色林组仅有一只犬在该事件时需要补救。术后 GCMPS-SF 评分总结于图2。LMM 分析显示总体组别（χ2(1)=4.72，p=0.030）、时间（χ2(7)=14.23，p=0.047）以及组别×时间交互作用（χ2(7)=15.19，p=0.034）效应均显著。采用 Bonferroni 校正对八个时间点进行逐时间点比较，发现在 T1（术后第一个小时评估，拔管后1.5 h）存在显著的组间差异，奥匹兰色林组的 GCMPS-SF 评分低于 N/S 组（中位数 1.0 [范围 1–1] 对 3.5 [范围 1–6]；估计平均差 2.50，95% CI 1.10–3.90；Bonferroni 校正 p=0.012）。其余时间点（T0、T2–T7；所有校正 p>0.05）未观察到显著的组间差异。次要结局 对 11 个手术事件的 ΔMAP 和 ΔHR 进行线性混合模型分析，显示组别 [ΔMAP：χ2(1)=6.44，p=0.011；ΔHR：χ2(1)=3.91，p=0.048] 和手术事件 [ΔMAP：χ2(10)=56.83，p<0.001；ΔHR：χ2(10)=23.89，p=0.008] 的总体效应均显著，表明血流动力学反应在组间和手术事件间均有变化。未检测到显著的组别×事件交互作用 [ΔMAP：χ2(10)=18.19，p=0.052；ΔHR：χ2(10)=12.71，p=0.241]，提示各事件间血流动力学变化模式在组间无显著差异。从数值上看，最明显的组间差异出现在 E2（第一枚睾丸外置），这是该手术模型中术中伤害性刺激最强的事件。在 E2 时，N/S 组 MAP 较基线平均升高 36.7±17.5 mmHg，而奥匹兰色林组平均升高 12.4±5.0 mmHg（估计平均差（β）24.4 mmHg，未校正 95% CI 9.2–39.5 mmHg；Bonferroni 校正 p=0.085）。类似地，图2 N/S 组（n=4，深色柱，实心圆）和奥匹兰色林组（n=4，浅色柱，空心圆）术后 Glasgow 复合疼痛量表-短表（GCMPS-SF）评分随时间的变化。数据以中位数（范围）表示；柱高及叠加圆表示中位数，误差线表示范围。水平虚线表示补救镇痛阈值（评分≥5）。T0，拔管后30 min；T1，T0后1 h；T2，T0后2 h；T3，T0后3 h；T4，T0后4 h；T5，T0后5 h；T6，T0后6 h；T7，T0后7 h。星号（*）表示 Bonferroni 校正后组间差异有统计学意义（校正 p<0.05）。N/S 组 HR 平均增加 35.6±21.9 次/min，而奥匹兰色林组为 8.6±6.1 次/min（估计平均差（β）27.0 次/min，未校正 95% CI 5.9–48.1 次/min；Bonferroni 校正 p=0.225）。这些差异在 Bonferroni 校正后未达到统计学显著性，应仅解释为数值趋势，这与本初步研究的探索性性质一致（图3）。N/S 组有一只犬需要单次术后补救镇痛干预，从 T1 至 T2 接受瑞芬太尼 CRI 1小时（总剂量：4 μg·kg−1），而奥匹兰色林组没有犬达到补救阈值。累积术后补救镇痛无显著差异 Frontiers in Veterinary Science 05 frontiersin.org
Lee 等，10.3389/fvets.2026.1954078，图3：在接受睾丸切除术并分别以 opiranserin（opiranserin 组，n=4）或生理盐水（N/S 组，n=4）作为围手术期镇痛的犬中，11 个预设手术事件期间平均动脉压（ΔMAP，A）和心率（ΔHR，B）的术中变化。数据以平均值±标准差表示。E1，第1侧皮肤切开；E2，第1睾丸外置；E3，撕脱第1睾丸附睾尾韧带；E4，钳夹第1睾丸精索；E5，切断第1睾丸精索；E6，第2侧皮肤切开；E7，第2睾丸外置；E8，撕脱第2睾丸附睾尾韧带；E9，钳夹第2睾丸精索；E10，切断第2睾丸精索；E11，伤口闭合。组间检测到消耗量差异（p=0.453）。关于不良反应，N/S 组中有1只犬各发生一次呕吐和恶心，另1只N/S组犬出现一次咂嘴。在 opiranserin 组中，1只犬各出现一次呕吐和恶心。组间不良反应发生率无显著差异（所有p>0.05）。术中麻醉管理：所有犬的麻醉深度全程保持充分，无犬需要增加呼气末异氟烷浓度。两组皮肤切开前的术中低血压均用麻黄碱处理。在 opiranserin 组中，4只犬中有3只接受了三次麻黄碱（0.05 mg·kg−1 静注），1只犬接受了两次，N/S 组给药次数相当。两组中均无犬接受格隆溴铵，且除标准术中保温措施外，无犬需要主动保温。讨论：本预试验研究的结果提示，opiranserin 可能为接受去势手术的犬提供围手术期镇痛益处。接受 opiranserin 的犬需要的术中补救镇痛干预更少，LMM 分析表明手术事件中的总体血流动力学反应更低。然而，经多重比较校正后，没有任何事件特异性的组间差异保持显著。术后 GCMPS-SF 评分分析也提示在恢复早期阶段可能存在镇痛益处，但样本量小、总体疼痛评分低以及补救事件数量有限，需谨慎解读。术中补救镇痛被选为主要结局，因为它代表一个离散的、临床可操作的事件——即认为需要补充镇痛的时点——提供了直接且可解释的术中镇痛充分性测量。采用 MAP 和 HR 同时升高的要求是为了提高补救标准的特异性，将补救给药限制在与伤害性反应一致的血流动力学变化，而非孤立的自主神经波动。尽管与单变量标准相比这可能降低敏感性，但其目的是尽量减少补救干预的次数，从而保持术中补救镇痛频率——主要结局——在组间的区分能力。术后 GCMPS-SF 评分被选为共同主要结局，因为 GCMPS-SF 是一种经过验证的多维疼痛评估工具，专门为犬开发并标准化，纳入了行为和生理指标，共同捕捉术后疼痛的临床负担（15）。这两个结局旨在互补覆盖 opiranserin 的围手术期镇痛特征，涵盖疼痛管理的术中及术后阶段。opiranserin 组需要的术中补救镇痛干预少于 N/S 组，提示 opiranserin 以 CRI 给药时可能提供术中的抗伤害感受作用。N/S 组的每只犬需要的补救干预均多于 opiranserin 组的任何犬，这种分离在 E2（第一只睾丸外置）——该手术模型中伤害性最强的事件——最为明显，所有四只 N/S 犬均需要补救，而 opiranserin 组仅一只犬需要。opiranserin 组的补救需求不仅更低，而且变异性更小，每只犬恰好在两个事件需要补救，而 N/S 组范围为三到九个。然而，每组仅四只犬，这些观察结果无法有把握地解读，需要在更大规模的研究中确认。在术后期间，仅在 T1 观察到 GCMPS-SF 评分的显著组间差异（Bonferroni 校正 p=0.012），opiranserin 组疼痛评分较低。其余时间点无显著差异可能反映去势相关的术后疼痛相对较轻，导致两组评分均较低，从而限制了检测组间差异的范围（20）。关于次要结局，LMM 分析显示组别和手术事件对血流动力学反应均有显著总体效应，无显著的组别×事件交互作用，表明虽然两组中血流动力学反应随手术事件而变化，但 opiranserin 广泛地《兽医科学前沿》06 frontiersin.org
Lee 等人（10.3389/fvets.2026.1954078）减弱了整体血流动力学伤害性反应。术后仅一只 N/S 组犬需要补救镇痛，而 opiranserin 组无犬需要；尽管该差异的方向与术中结果一致，但未达到统计学显著性（p=0.453），应谨慎解读，因为两组大多数犬均未达到补救阈值。两组间不良反应无显著差异这一结果仅为初步的，鉴于样本量极小，不能据此得出确切的安全性结论；需要在犬中进行专门的安全性和耐受性研究。为处理切皮前低血压而需要使用麻黄碱的情况在 opiranserin 组与 N/S 组之间相当，表明 opiranserin 未明显影响麻醉相关低血压的发生率。由于麻黄碱作用时间极短，且其末次给药至少在切皮前 5 分钟，此后未再给药，其短暂的升压效应在首次手术操作前已基本消退，因此未对基于事件的 MAP 和 HR 分析产生混杂影响。两组均无犬需要使用格隆溴铵或主动保温，进一步提示 opiranserin 未对术中心血管或体温调节稳定性产生不良影响。Opiranserin 的双重机制——抑制 GlyT2 和拮抗 5-HT2A——增强脊髓甘氨酸能抑制并减弱脊髓背角下行 5-羟色胺能疼痛易化，从而抑制伤害性传递（21–24）。由于该镇痛作用介导于脊髓背角而非脊髓上镇静通路，opiranserin 无已知的镇静特性，这在围手术期是一种潜在优势。本初步研究是 opiranserin 在伴侣动物物种中的首次临床研究。Kim 等人（10）已报道了 opiranserin 在犬中具有抗伤害性感受活性的初步证据，他们证明以 5 mg·kg−1·h−1 输注 4 小时（总累积剂量：20 mg·kg−1）期间机械性伤害性感受阈值持续升高，且从 60 分钟起抗伤害性感受效应超过小剂量瑞芬太尼。本研究将这些发现扩展至手术环境，其中 opiranserin 在显著更低的总累积剂量 8 mg·kg−1 下显示出围手术期镇痛活性的初步证据，给药方案为先以 5 mg·kg−1·h−1 负荷输注 1 小时，随后以 0.33 mg·kg−1·h−1 维持输注 9 小时。值得注意的是，胃肠道体征的发生率在数值上低于先前的犬研究：Kim 等人报告 6 只犬中 2 只出现呕吐、5 只出现类恶心体征，而本研究中 4 只犬仅 1 只出现任一一体征（10），尽管组间样本量不同无法直接比较。然而，由于生理盐水组也有一只犬出现恶心和呕吐，不能排除围手术期因素的贡献——包括吸入麻醉药的影响（公认的犬催吐触发因素）以及通过共享的神经激肽-1 和 P 物质信号通路介导的术后疼痛（25,26）。因此，opiranserin 组观察到的胃肠道体征是真正的药物相关不良反应还是围手术期偶发事件仍不确定。除总剂量较低外，该方案的时间分布特意设计为将药物暴露集中在围手术期。选择高初始输注速率以快速达到目标；模拟的平均合并血浆浓度在 1 小时升至约 1,307 ng·ml−1，短暂达到并略超过目标范围上限。快速达到相对较高的早期暴露被认为对起效很重要：在先前的大实验研究中，抗伤害性感受作用在 5 mg·kg−1·h−1 输注 4 小时期间逐渐产生，并从 60 分钟起超过小剂量瑞芬太尼（10）。因此，负荷期的安排使该时间间隔在手术刺激开始前已经过去。负荷期之后，大幅降低的维持速率使暴露降至操作上限以下。由于相关问题是个体间变异性是否会导致持续过度暴露，因此采用模拟分布的上尾而非均值进行评估：合并血浆浓度的第 95 百分位数在 1.25 小时约为 998 ng·ml−1，2 小时约为 825 ng·ml−1，5 小时约为 539 ng·ml−1，表明约 95% 的模拟动物从 1.25 小时起处于或低于上限。这种前负荷型分布旨在在伤害性输入最大的术中期间提供最高暴露，同时在术后观察期维持连续但逐渐降低的暴露。本研究存在若干局限性需要考虑。首先，术中瑞芬太尼补救的残余镇痛效应可能混杂了 N/S 组首次补救给药后后续手术事件的血流动力学评估；这是基于补救镇痛的术中评估设计固有的局限性。选择瑞芬太尼作为术中补救镇痛药是因为其起效快（约 1 分钟）和停药后消退快（3–10 分钟），这些特性可最大限度减少连续手术事件之间的残余镇痛效应（19）。鉴于瑞芬太尼血-效应部位平衡迅速，给药后短时间内即达峰效应；因此，后续手术事件在镇痛效应达峰后但完全消退前开始，以避免手术时间过度延长（19,27）。该方案是在尽量减少残余药物效应与维持可接受手术时长之间的务实折中；因此不能完全排除瑞芬太尼在手术事件之间的残余镇痛效应。除 E2 外，其他手术事件的血流动力学反应组间差异有限，可能部分反映了 N/S 组重复给予瑞芬太尼的混杂影响，这会独立于研究药物而钝化后续伤害性反应。这是基于补救镇痛的术中评估设计固有的局限性，在解读后续手术事件的 LMM 结果时应予以考虑。其次，犬去势模型与轻至中度术后疼痛相关，这可能降低了 GCMPS-SF 在所有术后时间点的区分敏感性；需要在 Frontiers in Veterinary Science 07 frontiersin.org 中进行验证
Lee 等，10.3389/fvets.2026.1954078 因此，有必要采用与更强伤害性刺激强度相关的手术模型（20）。第三，本研究仅在雄性比格犬中进行；对其他品种、体重、性别和手术模型的普适性需要进一步研究。第四，未测量奥匹兰色林的血浆浓度，因而无法确认实际达到的暴露量，并限制了对药代动力学-药效学特征的描述。目前尚无奥匹兰色林在犬中的已发表药代动力学数据；在健康人类志愿者中，0.25–8 mg·kg⁻¹ 剂量范围内的终末半衰期为 1.51 至 2.13 小时（5），但清除率、分布及靶受体药理学（GlyT2 和 5-HT2A）方面的种属差异仍未被阐明。因此，本研究使用的给药方案仍处于研究阶段。由于尚未建立犬的治疗浓度-反应关系，不应将其解释为优化的临床剂量，犬中的最佳剂量、给药间隔和给药途径仍有待通过专门的药代动力学和剂量探索研究来确定。第五，本研究缺乏阳性镇痛对照组；与已确立的围手术期镇痛药进行比较，可为评估奥匹兰色林镇痛效应的幅度提供参考基准。第六，样本量非常小（每组 n=4）且缺乏先验样本量计算，意味着本研究在大多数结局指标上不足以检出具有临床意义的差异；因此，统计学显著发现应被解释为产生假说，而非验证性结论。第七，省略阿片类药物术前用药和局部区域镇痛偏离了当前犬去势术多模式镇痛建议（1），并限制了这些发现的外部有效性。该设计对于分离奥匹兰色林的镇痛贡献是必要的，且所有犬均给予基线美洛昔康并采用预定的术中及术后补救方案，从而保障了动物福利；然而，结果不能直接适用于常规临床实践，因为在常规临床实践中会使用多模式镇痛。第八，在众多主要和次要结局指标上进行多重统计比较增加了 I 型错误的风险；在适当情况下应用了 Bonferroni 校正，但这不能完全减轻具有许多终点的探索性研究固有的假阳性风险升高。结论 在这项初步研究中，奥匹兰色林与接受去势术的犬术中补救镇痛需求减少相关，并提供了围手术期镇痛获益的初步证据，在术后首次每小时评估（T1）时观察到较低的术后疼痛评分。这些发现属于产生假说性质，需要在更大规模、具有足够把握度的研究中加以确认。数据可用性声明 原始数据将由通讯作者在合理请求下提供。伦理声明 本动物研究经首尔国立大学机构动物护理与使用委员会批准（IACUC 编号 SNU-250728-4-2）。动物的饲养和护理遵循《韩国实验动物法》指南。本研究按照当地法规和机构要求进行。作者贡献 SL：概念构思、数据管理、正式分析、研究实施、方法学、项目管理、软件、验证、撰写——初稿、撰写——审阅与编辑。SO：数据管理、研究实施、方法学、验证、撰写——审阅与编辑。IL：概念构思、数据管理、正式分析、资金获取、资源、监督、验证、可视化、撰写——审阅与编辑。W-GS：概念构思、数据管理、正式分析、资金获取、项目管理、资源、监督、验证、可视化、撰写——审阅与编辑。资金 作者声明本研究及/或其发表获得了财务支持。本研究由以下项目支持：首尔国立大学新聘教师启动基金；BK21 FOUR 项目；以及首尔国立大学兽医学院兽医科学研究所。致谢 本研究得到首尔国立大学新聘教师启动基金、BK21 FOUR 项目以及首尔国立大学兽医学院兽医科学研究所的支持，作者感谢首尔国立大学兽医临床科学系工作人员在动物护理和实验操作方面提供的协助。利益冲突 作者声明本工作接受了 Vivozon, Inc. 的资助。资助方在本研究中的参与如下：提供研究药物奥匹兰色林/VVZ-149，并参与给药方案设计。作者声明本工作在不存在任何可被解释为潜在利益冲突的商业或财务关系的情况下进行。生成式 AI 声明 作者声明在本手稿的创作过程中使用了生成式 AI。生成式 AI（Claude，Anthropic） Frontiers in Veterinary Science 08 frontiersin.org
Lee 等 10.3389/fvets.2026.1954078 被用于协助图件制备、语言润色和稿件组织。所有科学内容、数据和解释均由作者提供。本文图件旁提供的任何替代文本（alt 文本）均由 Frontiers 在人工智能支持下生成，并已尽合理努力确保准确性，包括在可能情况下由作者审核。如您发现任何问题，请联系我们。出版者注：本文中表达的所有主张仅为作者个人观点，并不必然代表其所属机构、出版者、编辑和审稿人的观点。本文中可能评估的任何产品或其制造商可能作出的任何主张，均未获得出版者保证或认可。参考文献 1. Monteiro BP, Lascelles BDX, Murrell J, Robertson S, Steagall PVM, 等。2022 年 WSAVA 疼痛识别、评估与治疗指南。J Small Anim Pract。（2023）64:177–254。doi: 10.1111/jsap.13566 2. Latremoliere A, Woolf CJ。中枢敏化：中枢神经可塑性产生的痛觉过敏发生器。J Pain。（2009）10:895–926。doi: 10.1016/j.jpain.2009.06.012 3. Gruen ME, Lascelles BDX, Colleran E, Gottlieb A, Johnson J, Lotsikas P, 等。2022 年 AAHA 犬猫疼痛管理指南。J Am Anim Hosp Assoc。（2022）58:55–76。doi: 10.5326/JAAHA-MS-7292 4. Simon BT, Steagall PV。阿片类镇痛药在小动物临床实践中的现状与未来。J Vet Pharmacol Ther。（2017）40:315–26。doi: 10.1111/jvp.12377 5. Oh J, Lee SH, Kim A, Yoon J, Jang K, Lee DH, 等。新型非阿片类镇痛药 VVZ-149 注射液在健康志愿者中的安全性、耐受性和药代动力学特征：一项首创、首次人体研究。J Clin Pharmacol。（2018）58:64–73。doi: 10.1002/jcph.973 6. Cioffi CL。抑制甘氨酸再摄取：通过增强甘氨酸介导的脊髓神经传递并减弱中枢伤害性信号传导来治疗疼痛的潜在途径。Biomolecules。（2021）11:864。doi: 10.3390/biom11060864 7. Heijmans L, Mons MR, Joosten EA。慢性神经病理性疼痛及脊髓电刺激后下行5-羟色胺能投射与脊髓伤害感受调节的系统综述。Mol Pain。（2021）17:17448069211043965。doi: 10.1177/17448069211043965 8. Song I, Cho S, Nedeljkovic SS, Lee SR, Lee C, Kim J, 等。新型镇痛分子 VVZ-149 在疼痛情感成分中的作用：腹腔镜及机器人腹腔镜胃切除术后疼痛的探索性概念验证研究结果。Pain Med。（2021）22:2037–49。doi: 10.1093/pm/pnab066 9. Lee HJ, Sim JY, Song I, Nedeljkovic SS, Kim DK, Oh AY, 等。首创镇痛分子 VVZ-149 减少腹腔镜结肠切除术后疼痛和阿片类药物消耗：一项确证性3期试验。J Clin Anesth。（2025）101:111729。doi: 10.1016/j.jclinane.2024.111729 10. Kim N, Oh S, Lee S, Lee S, Lee I, Son WG。奥匹兰色林（Unafra）对比格犬机械伤害性阈值的影响：一项随机交叉研究。Vet Anaesth Analg。（2026）53:101259。doi: 10.1016/j.vaa.2026.101259 11. Greenfield CL, Johnson AL, Schaeffer DJ。私人小动物专诊或主导执业兽医中各种操作、技能和知识领域的使用频率及对新兽医学院毕业生的熟练度期望。J Am Vet Med Assoc。（2004）224:1780–7。doi: 10.2460/javma.2004.224.1780 12. Gavet M, Cardinali M, Sentenac J, Bernady A, Conde Ruiz C, Allaouchiche B, 等。使用副交感神经张力活动指数评估去势麻醉犬的伤害感受-抗伤害感受平衡。Vet Anaesth Analg。（2022）49:597–607。doi: 10.1016/j.vaa.2022.08.009 13. Budsberg SC, Cross AR, Quandt JE, Pablo LS, Runk A。美洛昔康静脉给药用于犬膝关节手术后围手术期疼痛管理的评价。Am J Vet Res。（2002）63:1557–63。doi: 10.2460/ajvr.2002.63.1557 14. Huuskonen V, Hughes JML, Estaca Banon E, West E。睾丸内利多卡因可减少犬对手术去势的反应。Vet Anaesth Analg。（2013）40:74–82。doi: 10.1111/j.1467-2995.2012.00775.x 15. Reid J, Nolan AM, Hughes JML, Lascelles D, Pawson P, Scott EM。简短版格拉斯哥复合测量疼痛量表（CMPS-SF）的开发及镇痛干预评分的推导。Anim Welf。（2007）16:97–104。doi: 10.1017/S096272860003178X 16. Gesztesi Z, Mootz BL, White PF。瑞芬太尼输注用于颅内手术期间血流动力学控制。Anesth Analg。（1999）89:1282–7。doi: 10.1213/00000539-199911000-00038 17. Borges Conterno G, de Mello Copatti A, Gravi A, Mesquita LB, Bento RR, Molina GF, 等。瑞芬太尼与芬太尼作为犬卵巢子宫切除术全静脉麻醉一部分的比较。Cienc Rural。（2024）54:e20230124。doi: 10.1590/0103-8478cr20230020 18. Riccó Pereira CH, Lerche P。犬和猫。见：Lamont LA, Grimm KA, Robertson SA, 等编。兽医麻醉与镇痛。第6版。Wiley-Blackwell；（2024）。第1163–5页。doi: 10.1002/9781119830306.ch59 19. Battershill AJ, Keating GM。聚焦瑞芬太尼：其在重症监护病房中的镇痛和镇静用途。CNS Drugs。（2006）20:519–22。doi: 10.2165/00023210-200620060-00006 20. Quarterone C, Luna SPL, Crosignani N, de Oliveira FA, Lopes C, da Maia Lima AF, 等。犬和猫卵巢子宫切除术比睾丸切除术需要更多的术后镇痛。Can Vet J。（2017）58:1191–4。21. Mohammadzadeh A, Lakatos PP, Balogh M, Zádor F, Karádi DÁ, Zádori ZS, 等。在大鼠神经病理性疼痛模型中 GlyT-1 和 GlyT-2 抑制剂全身联合用药增强抗异常性疼痛的药理学证据。Int J Mol Sci。（2021）22:2479。doi: 10.3390/ijms22052479 22. Chater RPC, Peiser-Oliver J, Pati TK, Quinn AS, Lotsaris I, Frangos ZJ, 等。一种用于神经病理性疼痛且无靶点副作用的可逆性 GlyT2 变构抑制剂。Nat Commun。（2026）17:2828。doi: 10.1038/s41467-026-69616-5 23. Dong R, Yu B, Chen L, Yu W。大鼠切口痛模型中的5-HT2A受体-钾氯共转运体2信号通路。Exp Ther Med。（2016）12:3583–8。doi: 10.3892/etm.2016.3807 24. Song Z, Meyerson BA, Linderoth B。在大鼠神经病理性疼痛模型中参与脊髓电刺激镇痛作用的脊髓5-HT受体。Pain。（2011）152:1666–73。doi: 10.1016/j.pain.2011.03.012 25. Hay Kraus BL。聚焦枸橼酸马罗匹坦的围手术期应用。Vet Med。（2017）8:41–51。doi: 10.2147/VMRR.S126469 26. Davies JA, Fransson BA, Davis AM, Gilbertsen AM, Gay JM。犬术后反流和呕吐的发生率及危险因素：244例（2000–2012）。J Am Vet Med Assoc。（2015）246:327–35。doi: 10.2460/javma.246.3.327 27. Jeong HJ, Baik HJ, Kim JH, Kim YJ, Bahk JH。瑞芬太尼效应室浓度用于最大限度减少地氟烷吸入引起的心血管变化。Yonsei Med J。（2013）54:739–46。doi: 10.3349/ymj.2013.54.3.739 Frontiers in Veterinary Science 09 frontiersin.org
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TYPEOriginal Research PUBLISHED05 October 2026 DOI10.3389/fvets.2026.1954078 OPEN ACCESS EDITED BY Luca Pennasilico, University of Camerino, Italy REVIEWED BY Jane Quandt, University of Georgia, United States Stefanos G. Georgiou, University of Thessaly, Greece *CORRESPONDENCE Won-Gyun Son carpeego@snu.ac.kr RECEIVED31 July 2026 REVISED07 September 2026 ACCEPTED11 September 2026 PUBLISHED05 October 2026 CITATION Lee S, Oh S, Lee I and Son W-G (2026) Perioperative analgesic effects of opiranserin in canine castration: a pilot study.Front. Vet. Sci.13:1954078. doi: 10.3389/fvets.2026.1954078 COPYRIGHT ©2026 Lee, Oh, Lee and Son. This is an open-access article distributed under the terms of theCreative Commons Attribution License (CC BY).Theuse, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Perioperative analgesic effects of opiranserin in canine castration: a pilot study Seongwon Lee, Seonbin Oh, Inhyung Lee and Won-Gyun Son * Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea Introduction:Opiranserin, a non-opioid analgesic acting as a glycine transporter 2 inhibitor and 5-HT2A receptor antagonist, was evaluated for reducing intraoperative rescue analgesia and postoperative pain in dogs undergoing castration under isoflurane anesthesia. Materials and methods:Eight healthy male Beagle dogs were randomized to receive a continuous rate infusion of opiranserin (5 mg·kg −1 ·h −1 for 1 h before induction, then 0.33 mg·kg −1 ·h −1 for 9 h;n=4) or 0.9% saline (n=4). Anesthesia was induced with alfaxalone and maintained with isoflurane (1.5% end-tidal); all dogs received meloxicam and cefazolin preoperatively, without locoregional analgesia. Hemodynamic responses (MAP,HR) were recorded across 11 surgical events; rescue remifentanil was given when both increased≥20% from baseline. Postoperative pain was scored with the Glasgow Composite Measure Pain Scale–Short Form (GCMPS-SF) from 30 min after extubation (T0) through T7, with rescue analgesia at scores≥5. Primary outcomes were intraoperative rescue analgesia frequency and postoperative GCMPS-SF scores; secondary outcomes were intraoperative hemodynamic responses, postoperative rescue consumption, and adverse effects. Data were analyzed with Mann–WhitneyU tests and linear mixed models with Bonferroni-adjusted comparisons. Results:The opiranserin group required fewer intraoperative rescue interventions than the normal saline group (median 2 [2–2] vs. 6.5 [3–9];p =0.021). GCMPS-SF scores showed significant effects of group (p=0.030), time (p=0.047), and group×time interaction (p=0.034), with lower scores in the opiranserin group at T1 (adjustedp=0.012) but not at other time points. Among secondary outcomes, significant overall effects of group were found forMAP (p=0.011) andHR (p=0.048), and of surgical event for both (p <0.001 andp=0.008), with no group×event interaction; no individual event differed significantly after correction. Cumulative postoperative rescue analgesic consumption and the incidence of adverse effects did not differ between groups. Conclusion:These preliminary findings suggest that opiranserin may reduce intraoperative rescue analgesia requirements and attenuate postoperative pain in dogs, warranting confirmation in larger trials. The absence of significant adverse effects is reassuring but should be interpreted cautiously given the small sample size. KEYWORDS opiranserin, acute pain management, 5-HT2A antagonist, glycine transporter 2 inhibitor, intraoperative nociception, postoperative pain, canine castration, rescue analgesia Frontiers inVeterinary Science01frontiersin.org
Lee et al.10.3389/fvets.2026.1954078 Introduction Effective perioperative analgesia is essential in veterinary patients because inadequate pain control can increase sympathetic and neuroendocrine stress responses and contribute to central sensitization (1,2). Current guidelines recommend multimodal analgesia using opioids, non-steroidal anti-inflammatory drugs (NSAIDs), and local anesthetics as first-tier agents for acute surgical pain in dogs and cats (3). Among these, opioids have traditionally been considered the cornerstone of perioperative pain management, owing to their reliable and dose-dependent analgesic efficacy (4). Although opioids provide potent analgesia, their use may be limited by adverse effects including bradycardia, respiratory depression, dysphoria, vomiting, nausea, and salivation (4). These limitations have increased interest in non-opioid analgesics that can reduce perioperative nociception while minimizing opioid-related adverse effects. Opiranserin is a novel non-opioid analgesic that inhibits glycine transporter 2, thereby enhancing spinal glycinergic inhibition, and antagonizes the 5-hydroxytryptamine 2A receptor, thereby attenuating descending serotonergic pain facilitation (5–7). Several human clinical studies have examined the postoperative analgesic efficacy of opiranserin (8,9). In a phase 2 trial involving 59 patients undergoing laparoscopic gastrectomy, opiranserin significantly reduced postoperative pain intensity and decreased opioid consumption by 29.5% compared with placebo (8). In a subsequent phase 3 trial involving 284 patients undergoing laparoscopic colectomy, opiranserin reduced patient-controlled analgesia requests by 60.2% and opioid consumption by 30.8% (9). In veterinary medicine, however, only one study has evaluated its analgesic properties, demonstrating increased mechanical nociceptive thresholds in six Beagle dogs compared with both normal saline (negative control) and low-dose remifentanil (4 μg·kg −1 ·h −1 , positive control), with opiranserin exceeding remifentanil from 60 to 240 min of infusion (10). Thus, existing evidence remains confined to human postoperative clinical trials and a single experimental veterinary nociception model; opiranserin’s perioperative analgesic efficacy in an actual clinical surgical setting has not yet been evaluated. Safety data have also been reported for opiranserin. In the phase 1 single ascending dose study (single 4-h infusion of up to 8 mg·kg −1 ), drug-related adverse events occurred in 13 of 46 healthy volunteers (28.3%) and comprised somnolence, nausea, dizziness, and headache; all were mild and transient, occurred predominantly at the highest doses (6–8 mg·kg −1 ), and resolved after discontinuation (5). In the phase 2 and phase 3 trials, the incidence of treatment-emergent adverse events was comparable between the opiranserin and placebo groups, and events considered drug-related were infrequent and mild to moderate in severity, resolving without intervention (8,9). No serious adverse events attributed to opiranserin were reported in any trial. In the single experimental study conducted in Beagle dogs, the principal adverse effects of opiranserin were vomiting in two of six dogs and nausea-like signs in five of six dogs; all adverse effects resolved within 30 min of discontinuing the infusion, and no sedation, psychomimetic signs, or neurological signs were observed (10). Taken together, the available efficacy and safety data support further evaluation of opiranserin, but neither has been assessed in dogs undergoing surgery. Accordingly, the present study evaluated the perioperative analgesic efficacy of opiranserin in male dogs undergoing castration, one of the most commonly performed elective procedures in small animal practice (11). This model was selected because the nociceptive events are easy to detect and their intensity is minimally influenced by the surgeon, providing a standardized and reproducible surgical stimulus of mild-to-moderate anticipated postoperative pain with well-defined intraoperative nociceptive events that enable systematic hemodynamic monitoring (12). Within this framework, the primary outcomes were intraoperative rescue analgesia frequency and postoperative Glasgow Composite Measure Pain Scale–Short Form (GCMPS-SF) scores, chosen to capture analgesic efficacy during the intraoperative and postoperative phases, respectively. Secondary outcomes were changes in mean arterial pressure (MAP) and heart rate (HR) across 11 standardized surgical events, cumulative postoperative rescue analgesic consumption, and the incidence of adverse effects. Given the absence of prior clinical data, this pilot study was designed as an exploratory investigation to generate preliminary estimates of opiranserin’s perioperative analgesic effects in a clinical surgical setting. We hypothesized that continuous rate infusion (CRI) of opiranserin would reduce intraoperative rescue analgesia requirements and postoperative GCMPS-SF scores, attenuate hemodynamic responses to surgical stimulation, and decrease postoperative rescue analgesic consumption compared with normal saline. Materials and Methods Ethical approval All experimental procedures were approved by the Institutional Animal Care and Use Committee of Seoul National University (IACUC No. SNU-250728-4-2). Animals were housed and cared for in accordance with the guidelines of the Korean Laboratory Animal Act. Animals and study design Eight healthy, sexually intact male Beagle dogs were enrolled in this randomized, blinded, parallel-group controlled pilot study. In accordance with the pilot study design, four dogs were allocated to each group: a normal saline (N/S) group (n=4) and an opiranserin group (n=4). All dogs underwent castration under general anesthesia. Group allocation was determined by simple randomization using a random number table, performed by an independent third party not involved in the study. The allocation sequence was concealed from the surgeon, surgical assistant, anesthesiologist, and pain assessor throughout the study. All surgeries were performed by the same experienced veterinary surgeon, who had performed more than 50 canine castrations before the study, using a standardized Frontiers inVeterinary Science02frontiersin.org
Lee et al.10.3389/fvets.2026.1954078 open scrotal orchiectomy technique with a separate incision over each testis. Sample size Because no previous surgical study in dogs provided reliable estimates of the effect size and variability for the selected outcomes, a formala priorisample size calculation was not performed. Eight dogs, with four allocated to each group, were included in this exploratory pilot study to obtain preliminary estimates of treatment effects and variability while limiting animal use. Accordingly, the results were interpreted as preliminary and hypothesis-generating. Drug administration Opiranserin was diluted in normal saline and administered as a CRI beginning 1 h before anesthetic induction at a loading dose of 5 mg·kg −1 ·h −1 for 1 h, followed by a maintenance dose of 0.33 mg·kg −1 ·h −1 for 9 h. The N/S group received 0.9% saline at an equivalent volume and rate. Drug preparation was performed by a dedicated investigator blinded to group allocation. Dose selection and pharmacokinetic rationale The opiranserin dosing regimen was established using an exposure-based, model-informed approach informed by human clinical exposure data and canine pharmacokinetic simulations. In humans, combined plasma concentrations of opiranserin and its active metabolite VVZ-368 associated with analgesic efficacy have been reported at approximately 2,000–2,500 ng·ml −1 . Because systemic-to-CNS exposure relationships differ across species and canine CNS exposure was expected to be greater relative to systemic plasma concentration, a lower provisional systemic target of approximately 1,000–1,250 ng·ml −1 was selected for the initial infusion phase. This value was treated as a pragmatic design target rather than a validated canine therapeutic concentration. The regimen was designed as a two-phase infusion, with a loading phase intended to rapidly achieve pharmacologically relevant exposure before surgical stimulation and a lower maintenance phase intended to sustain exposure while limiting prolonged systemic accumulation. Monte Carlo pharmacokinetic simulations (100 virtual subjects), based on the combined exposure of opiranserin and VVZ-368, supported an initial infusion of 5 mg·kg −1 ·h −1 for 1 h followed by 0.33 mg·kg −1 ·h −1 for 9 h, corresponding to a total dose of approximately 8 mg·kg −1 over 10 hours. Anesthetic protocol Anesthesia was induced with alfaxalone (2 mg·kg −1 IV) and maintained with isoflurane at a fixed end-tidal concentration of 1.5%; all dogs breathed spontaneously throughout the procedure. The concentration was held constant so that hemodynamic responses to surgical events would reflect differences in analgesic efficacy rather than variation in anesthetic depth. Anesthetic depth was monitored continuously by jaw tone, palpebral reflex, eye position, and spontaneous movement. Isoflurane was to be increased in 0.1% increments if signs of insufficient depth were observed. No opioid premedication or locoregional analgesia was administered, in order to isolate the analgesic contribution of opiranserin from that of other agents. All dogs received meloxicam as a baseline analgesic, and standardized intraoperative and postoperative rescue analgesia was provided to any dog meeting the predefined criteria. Perioperative management Meloxicam (0.2 mg·kg −1 IV) was administered immediately after induction as a perioperative analgesic (13), and cefazolin (22 mg·kg −1 IV) was administered 30 min prior to skin incision as antimicrobial prophylaxis in accordance with the institutional protocol in place at the time of the study. Fluid therapy was administered using Lactated Ringer’s solution at 10 mL·kg −1 ·h −1 for 1 h prior to induction, then reduced to 5 mL·kg −1 ·h −1 from induction through the end of surgery. The protocol specified the following interventions for intraoperative complications: ephedrine (0.05 mg·kg −1 IV) for hypotension (MAP<60 mmHg); glycopyrrolate (5μg·kg −1 IV) for bradycardia accompanied by hypotension (HR<60 beats/min with concurrent MAP<60 mmHg); and active warming for hypothermia (rectal temperature<36.5 ◦ C). Body temperature was monitored continuously via rectal probe throughout anesthesia. Intraoperative nociception assessment Hemodynamic variables including MAP and HR were continuously monitored via an arterial catheter placed in the right dorsal pedal artery and recorded automatically using a vital-sign recording program (Vital Recorder R ). 11 standardized surgical events were manually recorded: E1, skin incision of the first side; E2, exteriorization of the first testis; E3, tearing of the ligament of the tail of the epididymis of the first testis; E4, clamping of the spermatic cord of the first testis; E5, transection of the spermatic cord of the first testis; E6, skin incision of the second side; E7, exteriorization of the second testis; E8, tearing of the ligament of the tail of the epididymis of the second testis; E9, clamping of the spermatic cord of the second testis; E10, transection of the spermatic cord of the second testis; and E11, wound closure (14). For each surgical event, the mean value of MAP and HR recorded during the 10 s immediately preceding the event was designated as the pre-event baseline. The maximum values of each variable from the time of the event until the onset of the next event were identified, and the absolute change from baseline (MAP andHR, expressed as absolute change in mmHg and beats/min, respectively) was calculated. Frontiers inVeterinary Science03frontiersin.org
Lee et al.10.3389/fvets.2026.1954078 Postoperative pain and adverse effects assessment Postoperative pain was assessed using the GCMPS-SF, a validated multidimensional pain assessment tool incorporating vocalization, attention to the painful area, mobility, response to touch, demeanor, and posture/activity (15). All assessments were performed by a single trained investigator who was blinded to group allocation throughout the study. Because dogs were individually housed in standard cages during the assessment period, and because interrupting the study CRI to permit ambulation would have altered exposure to the investigational treatment and confounded the results, the mobility subscale was omitted, reducing the maximum possible score from 24 to 20 points (15). Pain assessments were performed at 30 min post-extubation (T0) and hourly from T1 to T7, for a total of eight evaluations. The CRI was discontinued within 1 h after T7, and no further pain assessments were conducted thereafter. All dogs were fully conscious and capable of spontaneous movement at T0, confirming adequate recovery from anesthesia prior to the commencement of pain scoring. Sedation was not formally scored in this study. The occurrence of adverse effects, including vomiting, nausea, and lipsmacking, was recorded throughout the postoperative observation period (10). For each dog, the cumulative dose of remifentanil administered as postoperative rescue analgesia (expressed inμg·kg −1 )was recorded as the measure of postoperative rescue analgesic consumption. Rescue analgesia A simultaneous increase of≥20% in both MAP and HR from the pre-event baseline was defined as the criterion for administering intraoperative rescue analgesia (16). Remifentanil (0.5μg·kg −1 IV) was used as the rescue agent (17). The timing and total frequency of rescue analgesia were recorded. Postoperative rescue analgesia consisted of remifentanil administered as a CRI (4μg·kg −1 ·h −1 ) for 1 h, initiated when the GCMPS-SF score reached≥5atany scheduled assessment time point (15,18). If the score remained ≥5 at the subsequent hourly assessment, the CRI was maintained for an additional hour; if the score fell below 5, the CRI was discontinued. Remifentanil was selected as the postoperative rescue agent because its ultrashort duration of action (3–10 min) and rapid offset allow return to baseline analgesic status within each hourly assessment interval, thereby minimizing carryover effects on subsequent GCMPS-SF scoring (19). Statistical analysis The primary outcomes — intraoperative rescue analgesia frequency and postoperative GCMPS-SF pain scores — were analyzed as follows. Intraoperative rescue analgesia frequency was compared between groups using the Mann–WhitneyU- test, with the corresponding Hodges–Lehmann estimate of the median difference and its 95% confidence interval reported as the effect size. Postoperative GCMPS-SF scores were analyzed using a linear mixed model (LMM) with group, time (T0–T7), and their interaction as fixed effects and individual dog as a random intercept. Fixed effects were evaluated by likelihood ratio tests (χ 2 ) on models fitted by maximum likelihood estimation. Estimated marginal means and per-timepoint between-group contrasts were derived from the model fitted by restricted maximum likelihood estimation, with degrees of freedom obtained by the Kenward– Roger approximation, andp-values adjusted using the Bonferroni correction across the eight time points. The secondary outcomes — intraoperative hemodynamic responses, cumulative postoperative rescue analgesic consumption, and adverse effect incidence — were analyzed as follows. Intraoperative hemodynamic data were analyzed using an LMM with group (N/S group vs. opiranserin group), surgical event (E1–E11), and their interaction as fixed effects and individual dog as a random intercept, fitted using restricted maximum likelihood estimation; between-group differences at each surgical event were assessed using the estimated fixed effect coefficients (β) and associatedt-tests with df=6, withp-values adjusted using the Bonferroni correction across 11 surgical events. Cumulative postoperative rescue analgesic consumption and adverse effect incidence were compared between groups using the Mann–WhitneyU-test. Ap-value of<0.05 was considered statistically significant. Prior to fitting each LMM, the normality of residuals was assessed using the Shapiro–Wilk test, and homoscedasticity was evaluated by visual inspection of residual plots. The random intercept structure was selected as the most parsimonious model based on likelihood ratio testing. Confidence intervals are presented unadjusted for multiple comparisons and describe the precision of each individual estimate, whereasp-values are Bonferroni-adjusted across comparisons where indicated; consequently, an interval excluding the null value does not necessarily correspond to a significant adjustedp-value. Given the exploratory pilot design and the multiplicity of outcomes analyzed, all statistically significant findings should be interpreted with caution, as the risk of Type I error is inherently elevated in an underpowered study with numerous endpoints. Results Primary outcomes The mean surgical time was 26.5±8.5 min (range, 18–40 min). The opiranserin group required significantly fewer intraoperative rescue analgesia interventions than the N/S group [median 2 (range 2–2; all four dogs received rescue at exactly two events) vs. 6.5 (range 3–9); Hodges–Lehmann median difference 4.0 interventions, 95% CI 1.0–7.0; Mann–WhitneyU-test,p=0.021]. Across the 11 standardized surgical events, all four dogs in the opiranserin group received rescue analgesia at exactly two events each, although these rescue events occurred at different surgical steps among individual dogs. In contrast, N/S group dogs received rescue analgesia between three and nine times, with every individual in the N/S group exceeding the rescue count of any dog in the opiranserin group (Figure 1). Notably, at E2 (exteriorization of the first testis) — the most nociceptive event in this surgical model — all four dogs in the N/S group required at least one Frontiers inVeterinary Science04frontiersin.org
Lee et al.10.3389/fvets.2026.1954078 FIGURE 1 Intraoperative rescue analgesia frequencies per individual subject across surgical events. Filled circles (•) and open circles (◦) indicate rescue events in the N/S group (n=4) and opiranserin group (n=4), respectively. The dotted line separates the two groups. E1, skin incision of the 1st side; E2, exteriorization of the 1st testis; E3, tearing of the ligament of the tail of the epididymis of the 1st testis; E4, clamping of the spermatic cord of the 1st testis; E5, transection of the spermatic cord of the 1st testis; E6, skin incision of the 2nd side; E7, exteriorization of the 2nd testis; E8, tearing ofthe ligament of the tail of the epididymis of the 2nd testis; E9, clamping of the spermatic cord of the 2nd testis; E10, transection of the spermatic cord of the 2nd testis; E11, wound closure. rescue intervention, whereas only one dog in the opiranserin group required rescue at this event. Postoperative GCMPS-SF scores are summarized inFigure 2. LMM analysis revealed significant overall group (χ 2 (1)=4.72, p=0.030), time (χ 2 (7)=14.23,p=0.047), and group× time interaction (χ 2 (7)=15.19,p=0.034) effects. Per-timepoint comparisons with Bonferroni correction across the eight time points identified a significant between-group difference at T1 (the first hourly postoperative assessment, 1.5 h post-extubation), where the opiranserin group showed lower GCMPS-SF scores than the N/S group (median 1.0 [range 1–1] vs. 3.5 [range 1–6]; estimated mean difference 2.50, 95% CI 1.10–3.90; Bonferroni-adjustedp= 0.012). No significant between-group differences were observed at the remaining time points (T0, T2–T7; all adjustedp>0.05). Secondary outcomes Linear mixed model analysis ofMAP andHR across the 11 surgical events revealed significant overall effects of group [MAP: χ 2 (1)=6.44,p=0.011;HR:χ 2 (1)=3.91,p=0.048] and surgical event [MAP:χ 2 (10)=56.83,p<0.001;HR:χ 2 (10) =23.89,p=0.008], indicating that hemodynamic responses varied both between groups and across surgical events. No significant group×event interaction was detected [MAP:χ 2 (10)=18.19, p=0.052;HR:χ 2 (10)=12.71,p=0.241], suggesting that the pattern of hemodynamic change across events did not significantly differ between groups. Numerically, the most pronounced betweengroup differences were observed at E2 (exteriorization of the first testis), which represented the most nociceptive intraoperative stimulus in this surgical model. At E2, the N/S group exhibited a mean MAP increase of 36.7±17.5 mmHg from baseline, whereas the opiranserin group showed a mean increase of 12.4±5.0 mmHg (estimated mean difference (β) 24.4 mmHg, unadjusted 95% CI 9.2–39.5 mmHg; Bonferroni-adjustedp=0.085). Similarly, FIGURE 2 Postoperative Glasgow Composite Measure Pain Scale–Short Form (GCMPS-SF) scores over time in the N/S group (n=4, dark bars, filled circles) and opiranserin group (n=4, light bars, open circles). Data are presented as median (range); bar height and the superimposed circle indicate the median, and error bars indicate the range. The dashed horizontal line indicates the rescue analgesia threshold (score≥5). T0, 30 min after extubation; T1, 1 h after T0; T2, 2 h after T0; T3, 3 h after T0; T4, 4 h after T0; T5, 5 h after T0; T6, 6 h after T0; T7, 7 h after T0. An asterisk (*) indicates a statistically significant between-group difference after Bonferroni correction (adjustedp<0.05). HR increased by a mean of 35.6±21.9 beats/min in the N/S group compared with 8.6±6.1 beats/min in the opiranserin group (estimated mean difference (β) 27.0 beats/min, unadjusted 95% CI 5.9–48.1 beats/min; Bonferroni-adjustedp=0.225). These differences did not reach statistical significance after Bonferroni correction and should be interpreted as numerical trends only, consistent with the exploratory nature of this pilot study (Figure 3). One dog in the N/S group required a single postoperative rescue analgesia intervention, receiving remifentanil CRI for 1 hour from T1 to T2 (total dose: 4μg·kg −1 ), whereas no dog in the opiranserin group met the rescue threshold. No significant difference in cumulative postoperative rescue analgesic Frontiers inVeterinary Science05frontiersin.org
Lee et al.10.3389/fvets.2026.1954078 FIGURE 3 Intraoperative changes in mean arterial pressure (MAP,A) and heart rate (HR,B) at 11 predefined surgical events in dogs undergoing orchiectomy and receiving opiranserin (opiranserin group,n=4) or normal saline (N/S group,n=4) as perioperative analgesia. Data are expressed as mean±SD. E1, skin incision of the 1st side; E2, exteriorization of the 1st testis; E3, tearing of the ligament of the tail of the epididymis of the 1st testis; E4, clamping of the spermatic cord of the 1st testis; E5, transection of the spermatic cord of the 1st testis; E6, skin incision of the 2nd side; E7, exteriorization of the 2nd testis; E8, tearing of the ligament of the tail of the epididymis of the 2nd testis; E9, clamping of the spermatic cord of the 2nd testis; E10, transection of the spermatic cord of the 2nd testis; E11, wound closure. consumption was detected between groups (p=0.453). Regarding adverse effects, one dog in the N/S group experienced one episode each of vomiting and nausea, and one other N/S dog exhibited lip-smacking once. In the opiranserin group, one dog showed one episode each of vomiting and nausea. Adverse effect incidence did not differ significantly between groups (allp>0.05). Intraoperative anesthetic management Anesthetic depth remained adequate throughout in all dogs, and no dog required an increase in the end-tidal isoflurane concentration. Intraoperative hypotension before skin incision was managed with ephedrine in both groups. In the opiranserin group, three of four dogs received ephedrine (0.05 mg·kg −1 IV) on three occasions and one dog on two occasions, with a comparable number of doses administered in the N/S group. No dog in either group received glycopyrrolate, and no dog required active warming beyond the standard intraoperative warming measures. Discussion The findings of this pilot study suggest that opiranserin may provide perioperative analgesic benefit in dogs undergoing castration. Dogs receiving opiranserin required fewer intraoperative rescue analgesic interventions, and LMM analyses indicated lower overall hemodynamic responses across surgical events. However, no event-specific between-group difference remained significant after adjustment for multiple comparisons. Postoperative GCMPS-SF score analyses also suggested a potential analgesic benefit in the early recovery phase, although the small sample size, low overall pain scores, and limited number of rescue events warrant cautious interpretation. Intraoperative rescue analgesia was selected as a primary outcome because it represents a discrete, clinically actionable event — the point at which analgesic supplementation was deemed necessary — providing a direct and interpretable measure of intraoperative analgesic adequacy. The requirement for concurrent increases in both MAP and HR was adopted to enhance the specificity of the rescue criterion, restricting rescue administration to hemodynamic changes consistent with a nociceptive response rather than isolated autonomic fluctuations. Although this may reduce sensitivity compared with single-variable criteria, it was intended to minimize the number of rescue interventions and thereby preserve the discriminatory power of intraoperative rescue analgesia frequency — the primary outcome — between groups. Postoperative GCMPS-SF scores were selected as a co-primary outcome because the GCMPS-SF is a validated, multidimensional pain assessment tool specifically developed and standardized for use in dogs, incorporating behavioral and physiological indicators that collectively capture the clinical burden of postoperative pain (15). Together, these two outcomes were intended to provide complementary coverage of the perioperative analgesic profile of opiranserin, spanning both the intraoperative and postoperative phases of pain management. The opiranserin group required fewer intraoperative rescue analgesia interventions than the N/S group, suggesting that opiranserin may provide intraoperative antinociception when administered as a CRI. Every dog in the N/S group required more rescue interventions than any dog in the opiranserin group, and this separation was most evident at E2 (exteriorization of the first testis) — the most nociceptive event in this surgical model — where all four N/S dogs required rescue compared with only one opiranserin dog. The rescue requirement was not only lower but also less variable in the opiranserin group, in which each dog required rescue at exactly two events, whereas the N/S group ranged from three to nine. However, with only four dogs per group, these observations cannot be interpreted with confidence and warrant confirmation in larger studies. In the postoperative period, a significant between-group difference in GCMPS-SF scores was observed only at T1 (Bonferroni-adjusted p=0.012), with the opiranserin group showing lower pain scores. The absence of significant differences at the remaining time points may reflect the relatively mild postoperative pain associated with castration, which produced low scores in both groups and thus limited the scope for detecting a between-group difference (20). Regarding the secondary outcomes, LMM analysis revealed significant overall effects of both group and surgical event on hemodynamic responses, with no significant group×event interaction, indicating that while hemodynamic responses varied across surgical events in both groups, opiranserin broadly Frontiers inVeterinary Science06frontiersin.org
Lee et al.10.3389/fvets.2026.1954078 attenuated the overall hemodynamic nociceptive response. Postoperative rescue analgesia was required in only one N/S dog and in none of the opiranserin dogs; although the direction of this difference is consistent with the intraoperative findings, it did not reach statistical significance (p=0.453) and should be interpreted cautiously, as most dogs in both groups did not meet the rescue threshold. The absence of significant betweengroup differences in adverse effects is preliminary and cannot be used to draw definitive safety conclusions given the very small sample size; dedicated safety and tolerability studies in dogs are required. The requirement for ephedrine to manage pre-incision hypotension was comparable between the opiranserin and N/S groups, indicating that opiranserin did not appreciably influence the incidence of anesthetic-related hypotension. Because ephedrine has an ultrashort duration of action and its final administration preceded skin incision by at least 5 min, with no further doses thereafter, its transient pressor effect had largely dissipated before the first surgical event and therefore did not confound the event-basedMAP andHR analyses. No dog in either group required glycopyrrolate or active warming, further suggesting that opiranserin did not adversely affect intraoperative cardiovascular or thermoregulatory stability. Opiranserin’s dual mechanism — GlyT2 inhibition and 5- HT2A antagonism — enhances spinal glycinergic inhibition and attenuates descending serotonergic pain facilitation at the dorsal horn, thereby suppressing nociceptive transmission (21– 24). Because this analgesic action is mediated at the spinal dorsal horn rather than through supraspinal sedative pathways, opiranserin has no known sedative properties, a potential advantage in the perioperative setting. The present pilot study represents the first clinical investigation of opiranserin in a companion animal species. Preliminary evidence of antinociceptive activity of opiranserin in dogs has been reported by Kim et al. (10), who demonstrated sustained increases in mechanical nociceptive thresholds throughout a 4-h infusion at 5 mg·kg −1 ·h −1 (total cumulative dose: 20 mg·kg −1 ), with antinociceptive effects exceeding those of low-dose remifentanil from 60 min onward. The present study extends these findings to a surgical setting, in which opiranserin showed preliminary evidence of perioperative analgesic activity at a substantially lower total cumulative dose of 8mg·kg −1 , administered as a loading infusion of 5 mg·kg −1 ·h −1 for 1 h followed by a maintenance infusion of 0.33 mg·kg −1 ·h −1 for 9 h. Notably, the incidence of gastrointestinal signs was numerically lower than in the preceding canine study: whereas Kim et al. reported vomiting in 2 of 6 dogs and nausea-like signs in 5 of 6 dogs, only one of four dogs in the present study exhibited either sign (10), although the differing group sizes preclude direct comparison. However, as nausea and vomiting were also observed in one dog in the normal saline group, a contribution from perioperative factors — including the effects of inhalant anesthetic agents, a recognized trigger of emesis in dogs, as well as postoperative pain mediated through shared neurokinin-1 and substance P signaling pathways — cannot be excluded (25,26). Whether the gastrointestinal signs observed in the opiranserin group represent a true drugrelated adverse effect or an incidental perioperative event therefore remains uncertain. Beyond its lower total dose, the temporal profile of this regimen was deliberately shaped to concentrate drug exposure over the perioperative period. The high initial infusion rate was selected to reach the target rapidly; the simulated mean combined plasma concentration rose to approximately 1,307 ng·ml −1 at 1 h, transiently reaching and slightly exceeding the upper end of the target range. Rapid attainment of a relatively high early exposure was considered important for onset: in the preceding experimental study in dogs, antinociception developed progressively during a 4-h infusion at 5 mg·kg −1 ·h −1 and exceeded that of low-dose remifentanil from 60 min onward (10). The loading phase was therefore scheduled so that this interval had elapsed before surgical stimulation began. Following the loading phase, the substantially lower maintenance rate allowed exposure to decline below the operational ceiling. Because the relevant question was whether inter-individual variability could result in sustained over-exposure, the upper tail of the simulated distribution rather than the mean was used for this assessment: the 95th percentile of the combined plasma concentration was approximately 998 ng·ml −1 at 1.25 h, 825 ng·ml −1 at 2 h, and 539 ng·ml −1 at 5 h, indicating that approximately 95% of simulated animals were at or below the ceiling from 1.25 h onward. This front-loaded profile was intended to provide the highest exposure during the intraoperative period, when nociceptive input is greatest, while maintaining continuous but progressively lower exposure throughout the postoperative observation period. Several limitations of this study warrant consideration. First, the residual analgesic effects of intraoperative remifentanil rescue may have confounded hemodynamic assessments at surgical events subsequent to the first rescue administration in the N/S group; this represents an inherent constraint of rescue analgesia-based intraoperative assessment designs. Remifentanil was selected as the intraoperative rescue analgesic agent due to its rapid onset of action (approximately 1 min) and rapid offset following discontinuation (3–10 min), properties that minimize carry-over analgesic effects between successive surgical events (19). Given the rapid blood–effect site equilibration of remifentanil, peak effect is achieved shortly after administration; accordingly, the subsequent surgical event was initiated after the analgesic effect had peaked but prior to complete offset, to avoid excessive prolongation of surgical time (19,27). This protocol represents a pragmatic compromise between minimizing residual drug effects and maintaining acceptable operative duration; residual analgesic effects of remifentanil between surgical events therefore cannot be entirely excluded. The limited betweengroup differences in hemodynamic responses at surgical events other than E2 may partly reflect the confounding influence of repeated remifentanil administrations in the N/S group, which would have blunted subsequent nociceptive responses independently of the study drug. This represents an inherent limitation of rescue analgesia-based intraoperative assessment designs and should be considered when interpreting the LMM results at later surgical events. Second, the canine castration model is associated with mild-to-moderate postoperative pain, which may have reduced the discriminatory sensitivity of the GCMPS-SF across all postoperative time points; validation in Frontiers inVeterinary Science07frontiersin.org
Lee et al.10.3389/fvets.2026.1954078 surgical models associated with greater nociceptive intensity is therefore warranted (20). Third, this study was conducted exclusively in male Beagle dogs; generalizability to other breeds, body weights, sexes, and surgical models requires further investigation. Fourth, plasma concentrations of opiranserin were not measured, precluding confirmation of the exposure actually achieved and limiting pharmacokinetic–pharmacodynamic characterization. No published pharmacokinetic data exist for opiranserin in dogs; the terminal half-life in healthy human volunteers ranged from 1.51 to 2.13 h across doses of 0.25– 8mg·kg −1 (5), but species-specific differences in clearance, distribution, and target receptor pharmacology (GlyT2 and 5-HT2A) remain uncharacterized. Consequently, the regimen used in this study remains investigational. Because a canine therapeutic concentration–response relationship has not been established, it should not be interpreted as an optimized clinical dose, and the optimal dose, dosing interval, and route of administration in dogs remain to be determined through dedicated pharmacokinetic and dose-ranging studies. Fifth, the study lacked a positive analgesic control group; comparison with an established perioperative analgesic would have provided a reference benchmark for evaluating the magnitude of opiranserin’s analgesic effect. Sixth, the very small sample size (n=4 per group) and the absence of an a priorisample size calculation mean this study was not powered to detect clinically meaningful differences in most outcomes; statistically significant findings should therefore be interpreted as hypothesis-generating rather than confirmatory. Seventh, the omission of opioid premedication and locoregional analgesia deviates from current multimodal analgesic recommendations for canine castration (1) and limits the external validity of these findings. This design was necessary to isolate the analgesic contribution of opiranserin, and animal welfare was safeguarded by baseline meloxicam in all dogs and by predefined intraoperative and postoperative rescue protocols; nevertheless, the results are not directly applicable to routine clinical practice, in which multimodal analgesia would be used. Eighth, the multiplicity of statistical comparisons across numerous primary and secondary outcomes increases the risk of Type I error; Bonferroni correction was applied where appropriate, but this cannot fully mitigate the inflated false-positive risk inherent to an exploratory study with many endpoints. Conclusion In this pilot study, opiranserin was associated with reduced intraoperative rescue analgesia requirements and preliminary evidence of perioperative analgesic benefit in dogs undergoing castration, with lower postoperative pain scores observed at the first hourly postoperative assessment (T1). These findings are hypothesis-generating and require confirmation in larger, adequately powered studies. Data availability statement The original data will be made available by the corresponding author upon reasonable request. Ethics statement The animal study was approved by the Institutional Animal Care and Use Committee of Seoul National University (IACUC No. SNU-250728-4-2). Animals were housed and cared for in accordance with the guidelines of the Korean Laboratory Animal Act. The study was conducted in accordance with the local legislation and institutional requirements. Author contributions SL: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Software, Validation, Writing – original draft, Writing – review & editing. SO: Data curation, Investigation, Methodology, Validation, Writing – review & editing. IL: Conceptualization, Data curation, Formal analysis, Funding acquisition, Resources, Supervision, Validation, Visualization, Writing – review & editing. W-GS: Conceptualization, Data curation, Formal analysis, Funding acquisition, Project administration, Resources, Supervision, Validation, Visualization, Writing – review & editing. Funding The author(s) declared that financial support was received for this work and/or its publication. This study was supported by: New Faculty Startup Fund, Seoul National University; BK21 FOUR program; and Research Institute of Veterinary Science, College of Veterinary Medicine, SNU. Acknowledgments This research was supported by the New Faculty Startup Fund from Seoul National University, and the BK21 FOUR program and Research Institute of Veterinary Science, College of Veterinary Medicine, Seoul National University, and the authors thank the staff of the Department of Veterinary Clinical Sciences, Seoul National University, for their assistance with animal care and experimental procedures. Conflict of interest The author(s) declared that this work received funding from Vivozon, Inc. The funder had the following involvement in the study: provided study drug opiranserin/VVZ-149 and contributed to dosing-regimen design. The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Generative AI statement The author(s) declared that Generative AI was used in the creation of this manuscript. Generative AI (Claude, Anthropic) Frontiers inVeterinary Science08frontiersin.org
Lee et al.10.3389/fvets.2026.1954078 was used to assist with figure preparation, language refinement, and manuscript organization. All scientific content, data, and interpretations were provided by the author(s). Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us. Publisher’s note All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. References 1. Monteiro BP, Lascelles BDX, Murrell J, Robertson S, Steagall PVM, et al. 2022 WSAVA guidelines for the recognition, assessment and treatment of pain.JSmallAnim Pract.(2023) 64:177–254. doi: 10.1111/jsap.13566 2. Latremoliere A, Woolf CJ. Central sensitization: a generator of pain hypersensitivity by central neural plasticity.JPain.(2009) 10:895–926. doi: 10.1016/j.jpain.2009.06.012 3. Gruen ME, Lascelles BDX, Colleran E, Gottlieb A, Johnson J, Lotsikas P, et al. 2022 AAHA pain management guidelines for dogs and cats.J Am Anim Hosp Assoc.(2022) 58:55–76. doi: 10.5326/JAAHA-MS-7292 4. Simon BT, Steagall PV. The present and future of opioid analgesics in small animal practice.J Vet Pharmacol Ther.(2017) 40:315–26. doi: 10.1111/jvp.12377 5. Oh J, Lee SH, Kim A, Yoon J, Jang K, Lee DH, et al. Safety, tolerability, and pharmacokinetic characteristics of a novel nonopioid analgesic, VVZ-149 injections in healthy volunteers: a first-in-class, first-in-human study.JClinPharmacol.(2018) 58:64–73. doi: 10.1002/jcph.973 6. Cioffi CL. Inhibition of glycine re-uptake: a potential approach for treating pain by augmenting glycine-mediated spinal neurotransmission and blunting central nociceptive signaling.Biomolecules.(2021) 11:864. doi: 10.3390/biom11060864 7. Heijmans L, Mons MR, Joosten EA. A systematic review on descending serotonergic projections and modulation of spinal nociception in chronic neuropathic pain and after spinal cord stimulation.Mol Pain.(2021) 17:17448069211043965. doi: 10.1177/17448069211043965 8. Song I, Cho S, Nedeljkovic SS, Lee SR, Lee C, Kim J, et al. Role of VVZ-149, a novel analgesic molecule, in the affective component of pain: results from an exploratory proof-of-concept study of postoperative pain following laparoscopic and roboticlaparoscopic gastrectomy.Pain Med.(2021) 22:2037–49. doi: 10.1093/pm/pnab066 9. Lee HJ, Sim JY, Song I, Nedeljkovic SS, Kim DK, Oh AY, et al. Reduction of postoperative pain and opioid consumption by VVZ-149, first-in-class analgesic molecule: a confirmatory phase 3 trial of laparoscopic colectomy.J Clin Anesth.(2025) 101:111729. doi: 10.1016/j.jclinane.2024.111729 10. Kim N, Oh S, Lee S, Lee S, Lee I, Son WG. Effects of opiranserin (Unafra) on mechanical nociceptive thresholds in Beagle dogs: a randomized crossover study.Vet Anaesth Analg.(2026) 53:101259. doi: 10.1016/j.vaa.2026.101259 11. Greenfield CL, Johnson AL, Schaeffer DJ. Frequency of use of various procedures, skills, and areas of knowledge among veterinarians in private small animal exclusive or predominant practice and proficiency expected of new veterinary school graduates.J Am Vet Med Assoc.(2004) 224:1780–7. doi: 10.2460/javma.2004.224.1780 12. Gavet M, Cardinali M, Sentenac J, Bernady A, Conde Ruiz C, Allaouchiche B, et al. Evaluation of the nociception–antinociception balance using the parasympathetic tone activity index in dogs anaesthetized for castration.Vet Anaesth Analg.(2022) 49:597–607. doi: 10.1016/j.vaa.2022.08.009 13. Budsberg SC, Cross AR, Quandt JE, Pablo LS, Runk A. Evaluation of intravenous administration of meloxicam for perioperative pain management following stifle joint surgery in dogs.Am J Vet Res.(2002) 63:1557–63. doi: 10.2460/ajvr.2002. 63.1557 14. Huuskonen V, Hughes JML, Estaca Banon E, West E. Intratesticular lidocaine reduces the response to surgical castration in dogs.Vet Anaesth Analg.(2013) 40:74– 82. doi: 10.1111/j.1467-2995.2012.00775.x 15. Reid J, Nolan AM, Hughes JML, Lascelles D, Pawson P, Scott EM. Development of the short-form Glasgow Composite Measure Pain Scale (CMPS- SF) and derivation of an analgesic intervention score.Anim Welf.(2007) 16:97–104. doi: 10.1017/S096272860003178X 16. Gesztesi Z, Mootz BL, White PF. The use of a remifentanil infusion for hemodynamic control during intracranial surgery.Anesth Analg.(1999) 89:1282– 7. doi: 10.1213/00000539-199911000-00038 17. Borges Conterno G, de Mello Copatti A, Gravi A, Mesquita LB, Bento RR, Molina GF, et al. Remifentanil versus fentanyl as part of total intravenous anesthesia for ovariohysterectomy in dogs.Cienc Rural.(2024) 54:e20230124. doi: 10.1590/0103-8478cr20230020 18. Riccó Pereira CH, Lerche P. Dogs and cats. In: Lamont LA, Grimm KA, Robertson SA, et al., editors. Veterinary Anesthesia and Analgesia. 6th ed. Wiley-Blackwell; (2024). p. 1163–5. doi: 10.1002/9781119830306.ch59 19. Battershill AJ, Keating GM. Spotlight on remifentanil: its analgesic and sedative use in the intensive care unit.CNS Drugs.(2006) 20:519– 22. doi: 10.2165/00023210-200620060-00006 20. QuarteroneC,LunaSPL,CrosignaniN,deOliveiraFA,LopesC,daMaiaLimaAF, et al. Ovariohysterectomy requires more post-operative analgesia than orchiectomy in dogs and cats.Can Vet J.(2017) 58:1191–4. 21. Mohammadzadeh A, Lakatos PP, Balogh M, Zádor F, Karádi DÁ, Zádori ZS, et al. Pharmacological evidence on augmented antiallodynia following systemic cotreatment with GlyT-1 and GlyT-2 inhibitors in rat neuropathic pain model.Int J Mol Sci.(2021) 22:2479. doi: 10.3390/ijms22052479 22. Chater RPC, Peiser-Oliver J, Pati TK, Quinn AS, Lotsaris I, Frangos ZJ, et al. A reversible allosteric inhibitor of GlyT2 for neuropathic pain without on-target side effects.Nat Commun.(2026) 17:2828. doi: 10.1038/s41467-026-69616-5 23.DongR,YuB,ChenL,YuW.The5-HT2Areceptorpotassium-chloride cotransporter 2 signaling pathway in a rat incision pain model.Exp Ther Med.(2016) 12:3583–8. doi: 10.3892/etm.2016.3807 24. Song Z, Meyerson BA, Linderoth B. Spinal 5-HT receptors that contribute to the pain-relieving effects of spinal cord stimulation in a rat model of neuropathy.Pain. (2011) 152:1666–73. doi: 10.1016/j.pain.2011.03.012 25. Hay Kraus BL. Spotlight on the perioperative use of maropitant citrate.Vet Med. (2017) 8:41–51. doi: 10.2147/VMRR.S126469 26. Davies JA, Fransson BA, Davis AM, Gilbertsen AM, Gay JM. Incidence of and risk factors for postoperative regurgitation and vomiting in dogs: 244 cases (2000–2012).J Am Vet Med Assoc.(2015) 246:327–35. doi: 10.2460/javma.246.3.327 27. Jeong HJ, Baik HJ, Kim JH, Kim YJ, Bahk JH. Effect-site concentration of remifentanil for minimizing cardiovascular changes by inhalation of desflurane.Yonsei Med J.(2013) 54:739–46. doi: 10.3349/ymj.2013.54.3.739 Frontiers inVeterinary Science09frontiersin.org