BACKGROUND Ketamine, a widely used anaesthetic and analgesic agent, is known to improve the analgesic efficacy of opioids and to attenuate central sensitisation and opioid-induced hyperalgesia. Clinical use is, however, curtailed by unwanted psychomimetic effects thought to be mediated by N-methyl-D-aspartate (NMDA) receptor antagonism. KEA-1010, a ketamine ester-analogue designed for rapid offset of hypnosis through hydrolysis mediated break-down, has been shown to result in short duration sedation yet prolonged attenuation of nociceptive responses in animal models. Here we report on behavioural effects following KEA-1010 administration to rodents. METHODS KEA-1010 was compared with racemic ketamine in its ability to produce loss of righting reflex following intravenous injection in rats. Analgesic activity was assessed in thermal tail flick latency (TFL) and paw incision models when injected acutely and when co-administered with fentanyl. Tail flick analgesic assessment was further undertaken in morphine tolerant rats. Behavioural aberration was assessed following intravenous injection in rats undergoing TFL assessment and in auditory pre-pulse inhibition models. RESULTS KEA-1010 demonstrated an ED50 similar to ketamine for loss of righting reflex following bolus intravenous injection (KEA-1010 11.4 mg/kg [95% CI 10.6 to 12.3]; ketamine (racemic) 9.6 mg/kg [95% CI 8.5-10.9]). Duration of hypnosis was four-fold shorter in KEA-1010 treated animals. KEA-1010 prolonged thermal tail flick responses comparably with ketamine when administered de novo, and augmented morphine-induced prolongation of tail flick when administered acutely. The analgesic effect of KEA-1010 on thermal tail flick was preserved in opioid tolerant rats. KEA-1010 resulted in increased paw-withdrawal thresholds in a rat paw incision model, similar in magnitude yet more persistent than that seen with fentanyl injection, and additive when co-administered with fentanyl. In contrast to ketamine, behavioural aberration following KEA-1010 injection was largely absent and no pre-pulse inhibition to acoustic startle was observed following KEA-1010 administration in rats. CONCLUSIONS KEA-1010 provides antinociceptive efficacy in acute thermal and mechanical pain models that augments standard opioid analgesia and is preserved in opioid tolerant rodents. The NMDA channel affinity and psychomimetic signature of the parent compound ketamine is largely absent for KEA-1010.

中文翻译：

---

氯胺酮酯类似物KEA-1010保留止痛和镇静作用，但没有拟模拟作用。

背景技术已知氯胺酮是广泛使用的麻醉剂和镇痛剂，其可改善阿片样物质的镇痛效果并减弱中枢敏化和阿片样物质诱导的痛觉过敏。然而，临床使用由于不希望的拟精神病作用而减少，这些作用被认为是由N-甲基-D-天冬氨酸（NMDA）受体拮抗作用介导的。KEA-1010是一种氯胺酮酯类似物，旨在通过水解介导的分解作用快速抵消催眠作用，已被证明可在动物模型中产生较短的镇静作用，但延长了伤害感受的衰减。在这里，我们报告了对老鼠施用KEA-1010后的行为影响。方法将KEA-1010与消旋氯胺酮进行比较，比较其在大鼠静脉内注射后产生的正向反射丧失的能力。急性注射和与芬太尼合用时，在热甩尾潜伏期（TFL）和爪切口模型中评估镇痛活性。在吗啡耐受的大鼠中进一步进行了甩尾镇痛的评估。在接受TFL评估的大鼠和听觉脉冲前抑制模型中，静脉注射后评估行为异常。结果KEA-1010表现出与氯胺酮相似的ED50，在推注静脉内注射后失去了正向反射力（KEA-1010 11.4 mg / kg [95％CI 10.6至12.3]；氯胺酮（外消旋）9.6 mg / kg [95％CI 8.5- 10.9]）。在用KEA-1010治疗的动物中，催眠的持续时间缩短了四倍。从头开始给药时，KEA-1010与氯胺酮相比可延长热甩尾反应，而当急性给药时，可增加吗啡诱导的甩尾时间。在耐受阿片样物质的大鼠中保留了KEA-1010对热甩尾的镇痛作用。KEA-1010在大鼠爪切口模型中导致爪退出阈值增加，其大小相似但比芬太尼注射液更持久，并与芬太尼共同使用时加和。与氯胺酮相反，在注射KEA-1010后，大鼠基本上不存在行为异常，在大鼠中注射KEA-1010后未观察到对惊吓的脉冲前抑制作用。结论KEA-1010在急性热和机械性疼痛模型中具有抗伤害作用，可增强标准的阿片类镇痛作用，并保存在阿片类耐受性啮齿动物中。对于KEA-1010，母体化合物氯胺酮的NMDA通道亲和力和拟精神特征不存在。