Characterization of Toxicity with Spinal Opiates

描述（由申请人提供）：持续鞘内吗啡输注用于控制慢性疼痛。通过组织病理学和MRI，我们证明了在一个良好表征的犬模型中长期鞘内输注高浓度吗啡对脊髓实质没有影响，但导致了导管尖端近端的无菌肉芽肿（中性粒细胞和巨噬细胞）的浓度和时间依赖性发展，该肉芽肿来自硬脑膜-蛛网膜层。我们的研究表明，肉芽肿是由吗啡，氢吗啡酮，美沙酮和DAMGO，但不是芬太尼。基于离体和体内研究，我们认为肉芽肿是由脑膜血管炎性细胞外渗引起的。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形成的发生率。这项工作导致以下假设和拟议的工作。假设1.脑膜MC脱颗粒介导鞘内吗啡产生的肉芽肿。我们将评估SQ输注阻断MC脱颗粒和阿片受体激活的药物（纳洛酮）对吗啡诱发的肉芽肿的影响。假设2.鞘内吗啡诱导MC脱颗粒导致局部CSF-MC产物增加和血管细胞硬膜内流增加。我们将在对照条件下和鞘内注射吗啡的情况下，使用伽马照相机荧光成像测量腰椎CSF中MC脱粒产物以及111-铟标记的单核细胞流入硬脑膜和CSF的产物。假设3.由于芬太尼不产生肉芽肿或脱颗粒，该结构系列中的其他脂溶性较低的阿片类药物将表现类似。我们将研究阿芬太尼对体外硬膜MC脱粒和组胺释放以及28天输注后肉芽肿形成的影响。假设4.可乐定（α 2激动剂）和咪达唑仑（苯二氮卓类）抑制MC激活，这将减少肉芽肿形成。我们将研究可乐定或咪达唑仑联合给药对鞘内吗啡诱发肉芽肿形成的影响。假设5.肉芽肿的形成需要最低的吗啡浓度和最短的时间。较低浓度持续较长时间不会导致肉芽肿形成。我们将使用系列MRI来确定3个月暴露于具有最小28天责任的吗啡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引起的病理学提供了1）一种新的机制解释。2)CSF中炎性产物的测量可以提供肉芽肿形成的鉴别预测因子。3)芬太尼类药物的不同作用指出了处理这个问题的几种潜在疗法。项目叙述：持续脊髓输注吗啡是控制慢性疼痛的有力工具。然而，接受这种治疗的患者有发生脊柱肿块（肉芽肿）的风险，这可能会压迫脊髓。目前的研究旨在确定肉芽肿形成的机制，并指出预防肉芽肿形成的具体方法，这将增加这种重要疼痛治疗的效用并降低其风险。

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.