Characterization of Toxicity with Spinal Opiates

描述(申请人提供)：鞘内持续注射吗啡用于控制慢性疼痛。通过组织病理学和核磁共振成像，我们证明了鞘内长期注射高浓度吗啡对脊髓实质没有影响，但导致导管尖端附近的无菌性肉芽肿(中性粒细胞和巨噬细胞)出现浓度和时间依赖性的发展，起源于硬膜蛛网膜层。我们的研究表明，肉芽肿是由吗啡、氢吗啡、美沙酮和DAMGO诱发的，但不是芬太尼。根据体外和体内的研究，我们认为肉芽肿是由脑膜血管系统的炎性细胞渗出引起的。初步研究表明，SQ输注两种不同的肥大细胞(MC)稳定剂可降低肉芽肿的发生率。这项工作导致了以下假设和拟议的工作。假设1.脑膜MC脱颗粒参与了鞘内吗啡引起的肉芽肿。我们将评估SQ输注阻断MC脱颗粒和阿片受体激活(纳洛酮)的药物对吗啡诱发的肉芽肿的影响。假设2：鞘内吗啡诱导的MC脱颗粒导致局部脑脊液-MC产物增加和血管细胞硬膜内流入增加。我们将在对照条件下和鞘内注射吗啡的情况下，用伽玛照相闪烁技术测量腰椎脑脊液中MC脱颗粒的产物以及111-铟标记的单核细胞流入硬脑膜和脑脊液的情况。假设3：由于芬太尼不会引起肉芽肿或脱颗粒，该结构系列中其他脂溶程度较低的阿片类药物也会有类似的表现。我们将检查阿芬太尼对体外硬脑膜MC脱颗粒和组胺释放以及28天后肉芽肿形成的影响。假设4：可乐定(α2激动剂)和咪达唑仑(苯二氮卓类)抑制MC激活，这将减少肉芽肿的形成。我们将检查联合应用可乐定或咪达唑仑对鞘内吗啡诱发的肉芽肿形成的影响。假设5.肉芽肿的形成需要最低浓度的吗啡维持最短时间。持续较长时间的较低浓度不会导致肉芽肿形成。我们将使用系列核磁共振来确定3个月的吗啡暴露剂量是否会增加肉芽肿形成的风险。这些研究为慢性鞘内阿片类药物的病理提供了新的机制解释。2)脑脊液中炎性物质的检测可作为肉芽肿形成的鉴别预测指标。3)芬太尼类药物的不同疗效表明，有几种潜在的治疗方法可以解决这个问题。项目简介：持续脊椎注射吗啡是控制慢性疼痛的有力工具。然而，接受这种疗法的患者有发展成脊椎肿块(肉芽肿)的风险，这可能会压迫脊髓。目前的研究旨在明确肉芽肿形成的机制，并指出预防肉芽肿形成的具体方法，这将增加这一重要疼痛疗法的有效性和降低风险。

DESCRIPTION (provided by applicant): Continuous intrathecal morphine infusion is used in the control of chronic pain. By histopathology and MRI, we demonstrated that chronic intrathecal infusion of high concentrations of morphine in a well characterized canine model had no effect upon the spinal parenchyma, but led to the concentration and time dependent development of an aseptic granuloma (neutrophils and macrophages) proximal to the catheter tip, arising from the dura-arachnoid layer. Our studies show that granulomas are induced by morphine, hydromorphone, methadone and DAMGO, but not fentanyl. Based on ex vivo and in vivo work, we believe that the granuloma arises from extravasation of inflammatory cells from the meningeal vasculature. Preliminary work suggests that SQ infusion of two different mast cell (MC) stabilizers reduces the incidence of granuloma formation. This work leads to the following hypotheses and proposed work. Hypothesis 1. Meningeal MC degranulation mediates the granuloma produced by intrathecal morphine. We will assess effects on morphine-evoked-granuloma of SQ infusions of agents that block MC degranulation and opiate receptor activation (naloxone). Hypothesis 2. Intrathecal morphine induced MC degranulation leads to a local increase in CSF-MC products and an increased dural influx of vascular cells. We will measure products of MC degranulation in lumbar CSF and influx into dura and CSF of monocytes labeled with 111-Indium using gamma camera scintigraphy under control conditions and with intrathecal morphine. Hypothesis 3. As fentanyl does not produce granulomas or degranulation, other less lipid soluble opiates in this structural series will behave similarly. We will examine effects of alfentanil on ex vivo dural MC degranulation and histamine release and granuloma formation after 28 days of infusion. Hypothesis 4. Clonidine (alpha2 agonist) and midazolam (benzodiazepine) suppress MC activation and this will diminish granuloma formation. We will examine co-delivery of clonidine or midazolam on intrathecal morphine evoked granuloma formation. Hypothesis 5. Granuloma formation requires a minimum morphine concentration for a minimum period of time. Lower concentrations for more extended periods will not lead to granuloma formation. We will use serial MRIs to determine whether a 3-month exposure to a morphine dose having minimum 28-day liability increases the risk of granuloma formation. These studies provide 1) a novel mechanistic explanation for the pathology produced by chronic intrathecal opiates. 2) Measurement of inflammatory products in CSF may provide a differential predictor of granuloma formation. 3) The differential effects of the fentanyl like drugs points to several potential therapies for dealing with this problem. PROJECT NARRATIVE: Continuous spinal infusion of morphine is a powerful tool for controlling chronic pain. However, patients receiving this therapy are at risk for development of a spinal mass (a granuloma), which can compress the spinal cord. The present studies aim to define the mechanisms of granuloma formation and point to specific methods to prevent granuloma formation, which will increase the utility and reduce the risks of this important pain therapy.