RVM CCK and Neuropathic Pain

RVM CCK 和神经性疼痛

• 批准号: 6832666
• 负责人: JOSEPHINE LAI
• 金额: $ 35.57万
• 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 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6832666
• 关键词: autoradiography; behavior test; brain stem; cholecystokinin; hormone inhibitor; hormone receptor; hormone regulation /control mechanism; in situ hybridization; laboratory rat; microinjections; nerve injury; neural plasticity; neuropathology; neuropharmacology; opioid receptor; pain; receptor expression; spinal nerves; time resolved data

DESCRIPTION (provided by applicant): Recent evidence suggests 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-in jury 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 of a CCK 2 receptor 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 of mu opioid receptors. For these reasons, we hypothesize that nerve-injury results in a time-related increase in RVM 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.

描述(由申请人提供)：最近的证据表明，引发神经病理性疼痛的过程可能与维持这种疼痛的过程不同。持续神经病理性疼痛状态需要来自延髓头端腹内侧(RVM)的下行促进作用，这一发现表明，利多卡因在损伤后第6天(及以后)有效地阻断了实验性神经病理性疼痛，但在损伤后第3天却没有。这种下行促进作用的开始可能源于表达Mu阿片受体的RVM细胞的活动，因为无论是用皂苷-MU阿片结合物选择性损毁这些细胞，还是手术损毁背外侧索(DLF)(通往背角的下行纤维通路)，都可以防止和逆转神经病理性疼痛的表达。这些发现暗示了损伤后RVM下行易化过程的时间依赖性激活，以维持而不是启动异常疼痛。驱动这种疼痛的RVM神经可塑性的性质尚不清楚。这一机制的一个线索是我们观察到RVM微量注射CCK-2受体拮抗剂对已建立的神经病理性疼痛产生可逆性阻断。此外，向未损伤大鼠的右室微量注射CCK-8(S)可产生触觉和温度超敏反应，使人想起神经损伤引起的疼痛状态。这些效应可被损毁DLF或表达Mu阿片受体的RVM细胞所阻止，这表明RVM CCK可能通过激活由Mu阿片受体表达表型定义的RVM神经元来促进损伤诱导的疼痛。出于这些原因，我们假设神经损伤导致RVM CCK活性随时间的增加而增加，以驱动下行促进和维持神经损伤引起的疼痛。这一假设将通过以下具体目标进行检验。目的1研究(A)新生大鼠右室基础CCK活性，以及机械和热刺激对RVM CCK活性的影响，以及(B)神经损伤后RVM中CCK活性的时间依赖性。具体地说，将在脊髓神经结扎损伤后的早期和晚期测量基础CCK释放，以及RVM中对机械和热皮肤输入的CCK释放。目的2鉴定CCK受体(S)，在该受体上，RVM CCK可能起驱动下行易化作用。CCK和CCK2受体类型在RVM损伤前后的功能作用将通过微量注射选择性CCK受体拮抗剂进行药理学评估。CCK受体的空间分布将通过半定量原位杂交和受体放射自显影进行分析。目的2还将研究CCK受体与Mu阿片受体在RVM神经元中共定位的可能性。拟议的实验将揭示RVM可塑性的一些特征，这些特征可能对维持神经病理性疼痛至关重要。由于患有神经病理性疼痛的患者可能在突发性损伤发生后很长一段时间内才寻求治疗，因此了解维持神经病理性状态的机制对于开发合理的治疗干预措施至关重要。在这方面，拟议的实验可能揭示CCK受体拮抗剂在神经病理性疼痛治疗中的重要作用。