RVM CCK and Neuropathic Pain

RVM CCK 和神经性疼痛

• 批准号: 7426721
• 负责人: JOSEPHINE LAI
• 金额: $ 7.98万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-05 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7426721
• 关键词: Acute; Animals; Autoradiography; Behavior; Behavioral; Cells; Cholecystokinin; Cholecystokinin B Receptor; Cholecystokinin Receptor; Complex; Control Groups; Cutaneous; Data; Development; Driving neuroplasticity; Fiber; Human; Hypersensitivity; In Situ Hybridization; Injury; L364,718; Label; Lesion; Lidocaine; Ligation; Localized; Maintenance; Measures; Mechanics; Mediating; Messenger RNA; Microdialysis; Microinjections; Nature; Nerve; Neurons; Neuropathy; Nociception; Operative Surgical Procedures; Opioid; Opioid Receptor; Outcome; Pain; Pathway interactions; Patients; Peptides; Peripheral Nerves; Peripheral nerve injury; Phenotype; Process; Property; Rattus; Reading; Receptor Cell; Resolution; Role; Spatial Distribution; Spinal Cord; Spinal nerve structure; Stimulus; System; Tactile; Testing; Therapeutic Intervention; Time; Transcript; base; concept; cytotoxic; day; design; dorsal horn; in vivo; injured; mu opioid receptors; nerve injury; painful neuropathy; prevent; receptor; receptor expression; research study; response; sham surgery; transmission process

Recent evidence suggest that processes that initiate neuropathic pain may differ from those that maintain such pain. That persistent neuropathic pain states require descending facilitation arising from the rostral ventromedial medulla (RVM) is suggested by the finding that lidocaine injected into the RVM effectively blocks experimental neuropathic pain at post-inj ury day 6 (and later), but not at post-injury day 3. Onset of this descending facilitation may arise from activity of RVM cells that express mu opioid receptors, since either a selective lesion of these cells with a saporin-mu opioid conjugate or surgical lesion of the dorsolateral funiculus (DLF), a descending fiber pathway to the dorsal horn, prevents and reverses the expression of neuropathic pain. These findings implicate a time-dependent activation of descending facilitatory processes in the RVM following injury to maintain, rather than initiate, abnormal pain. The nature of the RVM neuroplasticity that drives such pain is unknown. One clue to this mechanism is our observation that RVM microinjection ofa CCK 2receptor antagonist produces a reversible blockade of established neuropathic pain. In addition, microinjection of CCK-8(S) into the RVM of uninjured rats produces tactile and thermal hypersensitivity reminiscent of states of nerve-injury induced pain. These effects are prevented by lesions of the DLF, or of RVM cells expressing mu opioid receptors, suggesting the possibility that RVM CCK may promote injury- induced pain by activating RVM neurons that are phenotypically defined by the expression ofmu opioid receptors. For these reasons, we hypothesize that nerve-injury results in a time-related increase in R VM CCK activity to drive descending facilitation and to maintain nerve-injury induced pain. This hypothesis will be tested by the following specific aims. Aim 1 will characterize (a) the basal CCK activity in the RVM, and changes in CCK activity in response to mechanical and thermal cutaneous inputs in naive rats, and (b) the time-dependent nature of CCK activity in the RVM following nerve injury. Specifically, basal CCK release, and CCK release in response to mechanical and thermal cutaneous inputs in the RVM will be measured at early and late time points after spinal nerve ligation injury. Aim 2 will identify the CCK receptor(s) at which RVM CCK may act to drive descending facilitation. The functional roles of CCK_ and CCK2 receptor types in the RVM pre- and post-injury will be evaluated pharmacologically by microinjection of selective CCK receptor antagonists. The spatial distribution of the CCK receptors will be analyzed by semi-quantitative in situ hybridization and receptor autoradiography. Aim 2 will also examine the possibility that CCK receptors may co-localize with mu opioid receptors in RVM neurons. The proposed experiments will reveal some features of the RVM plasticity that may be critical in maintaining neuropathic pain. As patients who suffer from neuropathic pain are likely to seek treatment long after the precipitating injury has occurred, understanding the mechanisms that maintain the neuropathic state will be essential for the development of rational therapeutic interventions. In this regard, the proposed experiments may reveal an important role for CCK receptor antagonists as therapy for neuropathic pain.

最近的证据表明，启动神经性疼痛的过程可能与维持这种疼痛的过程不同。的 持续性神经病理性疼痛状态需要由延髓头端腹内侧（RVM）引起的下行易化， 利多卡因注射到RVM有效地阻断了实验性神经病理性疼痛 第6天（及以后），但不是在损伤后第3天。这种下行易化的开始可能是由RVM细胞的活动引起的， 表达μ阿片受体，因为用皂草素-μ阿片缀合物选择性损伤这些细胞或手术损伤 背外侧索（DLF），一个下行的纤维通路的背角，阻止和逆转的表达， 神经性疼痛这些发现暗示了RVM下行易化过程的时间依赖性激活 在受伤后维持而不是引发异常疼痛。驱动这种疼痛的RVM神经可塑性的本质 不明这一机制的线索之一是我们观察到RVM微量注射CCK 2受体拮抗剂， 可逆性阻断已建立的神经性疼痛。另外，在正常对照组RVM内微量注射CCK-8（S）， 大鼠产生触觉和热超敏反应，使人联想到神经损伤诱导的疼痛状态。这些影响是 通过DLF或表达μ阿片受体的RVM细胞的病变来预防，这表明RVM CCK 可能通过激活RVM神经元来促进损伤诱导的疼痛，RVM神经元的表型由μ阿片样物质的表达来定义 受体。由于这些原因，我们假设神经损伤导致RVM CCK活性的时间相关性增加，以驱动 下行易化和维持神经损伤引起的疼痛。这一假设将通过以下具体测试进行检验： 目标。目的1将描述（a）RVM中的基础CCK活性，以及CCK活性响应于 机械和热皮肤输入在幼稚大鼠，和（B）的CCK活性的时间依赖性， 神经损伤后的RVM。具体而言，基础CCK释放和响应于机械和 在脊神经结扎后的早期和晚期时间点测量RVM中的热皮肤输入 损伤目的2将确定RVM CCK可能起作用以驱动下行易化的CCK受体。的 CCK_1和CCK_2受体类型在RVM损伤前后的功能作用将被评估 通过微量注射选择性CCK受体拮抗剂进行阻断。CCK的空间分布 通过半定量原位杂交和受体放射自显影术分析受体。Aim 2还将 检查CCK受体可能与RVM神经元中的μ阿片受体共定位的可能性。拟议 实验将揭示RVM可塑性的一些特征，这些特征在维持神经性疼痛中可能是至关重要的。as患者 患有神经性疼痛的人可能在诱发性损伤发生后很久才寻求治疗， 维持神经病状态的机制对于合理治疗干预的发展是必不可少的。 在这方面，所提出的实验可能揭示CCK受体拮抗剂作为神经病理性疾病治疗的重要作用。 痛苦