SYSTEMATIC STUDY OF SELECTIVE SPINAL ANALGESIA

描述：（改编自申请人的摘要）在过去的补助金 周期，研究者已完成临床前毒性筛选 用于鞘内（IT）新斯的明，并经皮穿刺证实 限制性的剂量依赖性镇痛， 与CSF新斯的明浓度显著相关。IT新斯的明 增加人CSF中的乙酰胆碱，大鼠研究表明 新斯的明诱导镇痛的毒蕈碱作用机制。它 新斯的明也能有效镇痛 人类和大鼠的激动剂。在这份提案中，调查人员将 从胆碱酯酶抑制转向单胺重摄取抑制， 使用阿米替林。IT阿米替林不引起行为镇痛 急性伤害性刺激，但协同增强 静脉注射吗啡镇痛如果全身性阿片类药物 激活球脊髓抑制性胺能通路。除了 单胺再摄取抑制，阿米替林是一种功能性NMDA 拮抗剂在体外，研究人员的初步数据表明， 阿米替林是抗伤害性的，与其他NMDA拮抗剂相似， 在各种痛觉过敏和异常性疼痛的动物模型中。这 提案将完成临床前毒性测试和安全性 评估IT阿米替林并测试其对急性伤害性感受的作用 单独疼痛，其与IV阿芬太尼在急性伤害性疼痛中的相互作用 疼痛，以及其单独对抗皮内辣椒素诱导的 痛觉过敏和异常性疼痛。这些影响将相互关联 CSF神经递质和阿米替林浓度， 人类机制的假定证据。此外该 IT阿米替林在伤害感受和 将在大鼠中详细评估痛觉过敏性疼痛。

DESCRIPTION: (Adapted from the applicant's abstract) In the past grant cycle, the investigators have completed preclinical toxicity screening for intrathecal (IT) neostigmine and demonstrated dermatomally restricted, dose dependent analgesia in humans, which correlated significantly with CSF neostigmine concentration. IT neostigmine increases acetylcholine in human CSF, and studies in rats demonstrate a muscarinic mechanism of action for neostigmine induced analgesia. IT neostigmine also potentates analgesia from intraspinal a2-adrenergic agonists in humans and rats. In this proposal, the investigators will turn from cholinesterase inhibition to monamine reuptake inhibition, using amitriptyline. IT amitriptyline causes no behavioral analgesia to acute noxious stimulation in rats, but synergistically enhances analgesia from IV morphine. This would be expected if systemic opioids activate bulbospinal inhibitory aminergic pathways. In addition to monoamine reuptake inhibition, amitriptyline is a functional NMDA antagonist in vitro, and the investigators preliminary data suggest that IT amitriptyline is antinociceptive, similar to other NMDA antagonists, in a variety of animal models of hyperalgesia and allodynia. This proposal will complete preclinical toxicity testing and safety assessment of IT amitriptyline and test its effect on acute nociceptive pain alone, its interaction with IV alfentanil in acute nociceptive pain, and its efficacy alone against intradermal capsaicin induced hyperalgesia and allodynia in humans. These effects will be correlated with CSF neurotransmitter and amitriptyline concentrations to provide presumptive evidence for mechanisms in humans. In addition, the pharmacological mechanisms of IT amitriptyline in nociceptive and hyperalgesic pain will be assessed in detail in rats.