Chronic morphine-induced sensitization of trigeminal dura sensitive neurons

描述(申请人提供)：药物过度使用头痛(MOH)是一种慢性的日常头痛，是由于经常使用治疗偏头痛疼痛的药物而发展起来的。尽管它具有临床意义，但MOH的潜在机制仍不清楚。我们假设，长期使用镇痛剂会导致神经系统的神经适应性变化，导致参与头痛的神经元的兴奋性增加。尽管一些研究已经提供了慢性吗啡诱导的伤害性信号敏化的间接证据，但缺乏直接的电生理学证据。利用细胞外单个单位记录，拟议的实验将检查持续给药对大鼠三叉神经脊束核(VSP)神经元与头痛有关的特性的影响。我们将测试这一假说，即持续的吗啡给药上调了伤害性感受器，如硬脑膜敏感的VSP神经元兴奋性的增加(目标1)。其他实验将检验这一假说，即在持续吗啡暴露后，VSP硬脑膜敏感神经元的兴奋性增加需要从头端延髓腹内侧部(RVM)下行促进(目标2)。作为这些目标的一部分，我们还将测试这一假设，即慢性吗啡诱导的RVM下行易化性增加干扰了反刺激，其定义是通过应用远程伤害性刺激抑制硬脑膜敏感神经元。值得注意的是，慢性日常头痛的患者被证明缺乏对反刺激产生的疼痛的正常抑制。这项研究的总体目标是研究慢性药物暴露如何在硬脑膜敏感神经元中产生神经适应性变化，从而可能导致头痛频率增加。药物过量头痛是一个主要的临床问题，影响到1%-2%的普通人口，可能是由过度使用阿片类药物、Triptans和非处方止痛药引起的。拟议中的实验将深入了解持续的吗啡暴露如何调节与头痛相关的神经通路。了解慢性吗啡暴露引起的神经适应性变化，将为治疗头痛患者提供新的治疗策略，同时降低发生MOH的风险。

DESCRIPTION (provided by applicant): Medication overuse headache (MOH) is a chronic daily headache that develops from the frequent use of medications taken for the treatment of migraine headache pain. Despite its clinical significance, the underlying mechanisms of MOH remain unknown. We hypothesize that chronic use of analgesics leads to neuro-adaptive changes in the nervous system that causes an increase in the excitability of neurons involved in headache pain. Although several studies have provided indirect evidence for chronic morphine-induced sensitization of nociceptive signals, direct electrophysiological evidence is lacking. Using extracellular single unit recordings, the proposed experiments will examine the effects of sustained morphine administration in rats on the properties of spinal trigeminal nucleus (Vsp) neurons relevant to headache pain. We will test the hypothesis that sustained morphine administration up-regulates pronociceptive systems, as indicated by an increase in the excitability of dura sensitive Vsp neurons (Aim 1). Additional experiments will test the hypothesis that descending facilitation from the rostral ventromedial medulla (RVM) is necessary for the increased excitability of Vsp dura sensitive neurons following sustained morphine exposure (Aim 2). As part of these aims we will also test the hypothesis that chronic morphine induced increases in descending facilitation from the RVM interferes with counter-irritation, as defined by the inhibition of dura sensitive neurons produced by the application of a remote noxious stimulus. Significantly, patients with chronic daily headache have been shown to lack the normal inhibition of pain produced by counter-irritation. The overall goal of this research is to study how chronic drug exposure can produce neuro-adaptive changes in dura sensitive neurons that may lead to an increased frequency of headaches. Medication overuse headache represents a major clinical problem, affecting 1-2 percent of the general population, and can be caused by overuse of opiates, triptans and "over-the-counter" analgesics. The proposed experiments will provide insight into how sustained morphine exposure can modulate headache-related neural pathways. Understanding the neuro-adaptive changes that occur with chronic morphine exposure will lead the way to new therapeutic strategies to treat headache patients while reducing the risk of developing MOH.