Psychostimulants induce long-term changes in nociception.

描述(申请人提供)：精神刺激剂，如哌醋甲酯(MPH)和甲基苯丙胺，被广泛使用和滥用。滥用甲基苯丙胺对健康的短期不良影响是众所周知的。尽管对长期影响的了解要少得多，但疼痛调制的变化似乎是一个潜在的重要后果。我们的初步数据显示，长期给予幼鼠MPH可增强吗啡的抗伤害性，并促进成年后对吗啡的耐受性的发展。行为学和解剖学数据表明，多巴胺和阿片类药物在中脑导水管周围灰质(PAG)相互作用。多巴胺是精神刺激剂作用的神经递质。这项建议中的研究集中在PAG作为一种新的共享神经生物底物，介导与精神刺激剂使用相关的疼痛调制的变化。腹外侧部PAG对阿片类药物的镇痛至关重要，也含有内源性多巴胺能神经元，可能是精神刺激剂药物的靶点。因此，PAG代表了多巴胺和痛觉调制的交汇点。阿片类药物效力的改变或基础疼痛状态的改变可能导致吗啡抗伤害性和耐受性的改变。该提案使用协作团队科学方法在电生理、解剖学和行为学水平上检查PAG功能。目标1的实验将侧重于阿片耐受性的变化，以及阿片受体效力和精神刺激剂给药后的脱敏。Aim#2中的实验将测试心理刺激剂通过改变PAG的神经处理来增强慢性疼痛的假设。最后，第三个目标将验证这样的假设，即结合慢性精神刺激剂给药和慢性疼痛将在PAG中产生多巴胺和阿片系统之间的独特相互作用。这些研究将阐明PAG中阿片类药物/多巴胺相互作用的细胞底物，以及这些细胞如何融入构成药物滥用对疼痛的长期后果的中央网络。我们将测试整个假设，即PAG是慢性精神刺激剂使用产生的伤害性和止痛性变化的关键底物。拟议的研究将更好地了解导致有药物滥用史患者慢性疼痛的细胞机制，从而开发有效的治疗方法。) 公共卫生相关性：精神刺激剂，包括哌醋甲酯(MPH)和甲基苯丙胺，是通常被滥用的药物，可以增强阿片类药物的镇痛作用。然而，很少有研究涉及精神刺激剂的使用和滥用对内源性疼痛通路的长期后果。我们的初步数据表明，先前使用精神刺激剂会增加对阿片类药物的耐受性，可能会导致更多的慢性疼痛患者对阿片类止痛剂产生抗药性。鉴于精神刺激剂的广泛使用和滥用，在这一人群中，长期遭受慢性疼痛和相关医疗费用的潜在风险是巨大的。)

DESCRIPTION (provided by applicant): Psychostimulants, such as methylphenidate (MPH) and methamphetamine, are widely used and abused. The short-term adverse health effects of methamphetamine abuse are well known. Although much less is known about the long-term effects, changes in pain modulation appear to be a potentially important consequence. Our preliminary data show that chronic administration of MPH to young rats enhances morphine antinociception and facilitates the development of tolerance to morphine as adults. Behavioral and anatomical data suggest that dopamine, the neurotransmitter underlying the effects of psychostimulants, and opioids interact in the periaqueductal gray (PAG). The studies in this proposal focus on the PAG as a novel shared neurobiological substrate mediating changes in pain modulation associated with psychostimulant use. The ventrolateral PAG is critical for opioid analgesia and also contains intrinsic dopaminergic neurons that are a likely target of psychostimulant drugs. Thus, the PAG represents a site of convergence between dopamine and pain modulation. Changes in morphine antinociception and tolerance could be caused by changes in opioid potency or changes in basal pain states. This proposal uses a collaborative team science approach to examine PAG function at electrophysiological, anatomical, and behavioral levels. Experiments in Aim #1 will focus on changes in opioid tolerance, as well as opioid receptor potency and desensitization following psychostimulant administration. Experiments in Aim #2 will test the hypothesis that psychostimulants enhance chronic pain via changes in neural processing in the PAG. Finally, Aim #3 will test the hypothesis that combining chronic psychostimulant administration and chronic pain will produce unique interactions between dopamine and opioid systems in the PAG. These studies will clarify the cellular substrates for opioid/dopamine interactions in the PAG and how these cells fit into the central networks that underlie the long- term consequences of drug abuse on pain. We will test the overall hypothesis that the PAG is a critical substrate for the changes in nociception and analgesia produced by chronic psychostimulant use. The proposed studies will provide a better understanding of the cellular mechanisms that contribute to chronic pain in patients with a history of drug abuse so effective treatments can be developed. ) PUBLIC HEALTH RELEVANCE: Psychostimulants, including methylphenidate (MPH) and methamphetamine are commonly abused drugs that can enhance opioid analgesia. However, few studies have addressed the long-term consequences of psychostimulant use and abuse on endogenous pain pathways. Our preliminary data demonstrate that prior psychostimulant use increases the development of tolerance to opioids, potentially resulting in increased numbers of chronic pain patients resistant to opioid analgesics. Given the widespread use and abuse of psychostimulants, the potential long-term suffering from chronic pain and associated healthcare costs in this population are enormous. )