Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, United States.
Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, United States.
Neurosci Lett. 2022 May 1;778:136617. doi: 10.1016/j.neulet.2022.136617. Epub 2022 Apr 4.
In rodent models, conditioning with acute footshock (AFS) has been demonstrated to produce bladder hypersensitivity which is more robust when rats, tested as adults, had also been pretreated with neonatal bladder inflammation (NBI). The spinal neurochemical mechanisms of pro-nociceptive processes in rats pretreated with NBI are not fully known and so the present study administered intrathecal (IT) opioid (naloxone) and NMDA receptor (MK-801) antagonists to determine whether these receptors' actions had been altered by NBI. Female Sprague-Dawley rat pups were intravesically pretreated on postnatal days P14-P16 with a 1% zymosan solution or with control procedures and then raised to adulthood (12-15 weeks of age). Bladder hypersensitivity was induced through use of an AFS paradigm. Visceromotor responses (VMRs; abdominal muscle contractions) to graded, air pressure-controlled urinary bladder distension were used as nociceptive endpoints. Immediately following AFS pretreatments, rats were anesthetized and surgically prepared. Pharmacological antagonists were administered via an IT catheter onto the lumbosacral spinal cord and VMRs determined 15 min later. Administration of IT naloxone hydrochloride (10 μg) to rats which had been pretreated only with AFS resulted in VMRs that were more robust than VMRs in similarly pretreated rats that received IT normal saline. In contrast, IT naloxone had no significant effect on rats that had been pretreated with both NBI&AFS, although MK-801 was inhibitory. These effects of IT naloxone suggest the presence of inhibitory influences in normal rats that are absent in rats pretreated with NBI. Absence of inhibitory influences produced by AFS was also demonstrated in rats pretreated with NBI&AFS using measures of thermal paw withdrawal latency (PWL): rats pretreated with only AFS had longer PWLs than rats pretreated with both NBI&AFS. Together, a reduction in anti-nociceptive mechanisms coupled with pro-nociceptive NMDA-linked mechanisms results in more robust nociceptive responses to distension in rats which had experienced NBI.
在啮齿动物模型中，已证实条件性足底电击（AFS）可导致膀胱过敏，而当成年大鼠在接受新生膀胱炎症（NBI）预处理后进行测试时，这种过敏更为明显。接受 NBI 预处理的大鼠中，促进伤害性感受过程的脊髓神经化学机制尚不完全清楚，因此本研究给予鞘内（IT）阿片类（纳洛酮）和 NMDA 受体（MK-801）拮抗剂，以确定 NBI 是否改变了这些受体的作用。雌性 Sprague-Dawley 幼鼠在出生后第 14-16 天，通过膀胱内给予 1%酵母聚糖溶液或对照程序进行预处理，然后长至成年期（12-15 周龄）。使用 AFS 范式诱导膀胱过敏。内脏运动反应（VMR；腹肌收缩）作为伤害性终点，用于评估逐渐增加的、气压控制的膀胱扩张。在 AFS 预处理后，立即对大鼠进行麻醉并进行手术准备。通过 IT 导管将药理学拮抗剂注入腰骶脊髓，并在 15 分钟后测定 VMR。向仅接受 AFS 预处理的大鼠给予 IT 盐酸纳洛酮（10μg）后，VMR 比接受 IT 生理盐水的类似预处理大鼠的 VMR 更为明显。相反，IT 纳洛酮对同时接受 NBI 和 AFS 预处理的大鼠没有显著影响，尽管 MK-801 有抑制作用。IT 纳洛酮的这些作用表明，正常大鼠中存在抑制性影响，而在接受 NBI 预处理的大鼠中则不存在。在接受 NBI 和 AFS 预处理的大鼠中，通过热足潜伏期（PWL）测量也证明了 AFS 产生的抑制性影响缺失：仅接受 AFS 预处理的大鼠的 PWL 长于同时接受 NBI 和 AFS 预处理的大鼠。总之，减轻抗伤害性机制，加上促进伤害性的 NMDA 相关机制，导致经历 NBI 的大鼠对扩张的伤害性反应更为明显。
