Chronic morphine-induced sensitization of trigeminal dura sensitive neurons

描述（由申请人提供）：药物过度使用性头痛（MOH）是一种慢性日常头痛，由频繁使用治疗偏头痛的药物引起。尽管其临床意义，MOH的潜在机制仍然未知。我们推测，长期使用镇痛药导致神经系统的神经适应性变化，导致头痛相关神经元兴奋性增加。虽然一些研究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证据。采用细胞外单单位记录技术，研究吗啡持续给药对大鼠三叉神经脊束核（VSP）神经元头痛相关特性的影响。我们将测试的假设，持续的吗啡管理上调pronociceptive系统，所示的硬膜敏感VSP神经元的兴奋性增加（目的1）。额外的实验将测试这一假设，即从延髓头端腹内侧（RVM）的下行促进是必要的持续吗啡暴露后的Vsp硬脑膜敏感神经元的兴奋性增加（目的2）。作为这些目标的一部分，我们还将测试的假设，慢性吗啡诱导的RVM下降促进的增加干扰反刺激，定义为由应用远程伤害性刺激产生的硬脑膜敏感神经元的抑制。值得注意的是，患有慢性每日头痛的患者已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，这可能导致头痛频率增加。药物过度使用头痛是一个主要的临床问题，影响1- 2%的普通人群，可能是由于过度使用阿片类药物，曲坦类药物和“非处方”止痛药引起的。拟议的实验将提供深入了解如何持续吗啡暴露可以调节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.