Psychostimulants induce long-term changes in nociception.

描述（由申请人提供）：精神兴奋剂，如哌醋甲酯（MPH）和甲基苯丙胺，被广泛使用和滥用。滥用甲基安非他明对健康的短期不利影响是众所周知的。虽然对长期影响知之甚少，但疼痛调制的变化似乎是一个潜在的重要后果。我们的初步数据表明，慢性管理的MPH年轻大鼠增强吗啡抗伤害感受，促进发展的耐受性吗啡作为成年人。行为和解剖学数据表明，多巴胺，神经递质潜在的精神兴奋剂的影响，阿片类药物相互作用的导水管周围灰质（PAG）。本提案中的研究重点是PAG作为一种新型的共享神经生物学底物，介导与精神兴奋剂使用相关的疼痛调制变化。腹外侧PAG对于阿片类镇痛是至关重要的，并且还包含可能是精神兴奋剂药物的靶点的内在多巴胺能神经元。因此，PAG代表多巴胺和疼痛调节之间的会聚位点。吗啡镇痛和耐受性的变化可能是由阿片效力的变化或基础疼痛状态的变化引起的。该提案使用协作团队科学方法来检查PAG在电生理学，解剖学和行为水平上的功能。目标1中的实验将集中于阿片耐受性的变化，以及精神兴奋剂给药后阿片受体效力和脱敏。目标#2中的实验将测试精神兴奋剂通过PAG中神经处理的变化增强慢性疼痛的假设。最后，目标#3将检验以下假设：将慢性精神兴奋剂给药和慢性疼痛组合将在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枢网络。我们将测试的总体假设，PAG是一个重要的基板的变化，伤害性和镇痛产生的慢性精神兴奋剂的使用。拟议的研究将更好地了解导致有药物滥用史的患者慢性疼痛的细胞机制，以便开发有效的治疗方法。) 公共卫生相关性：精神兴奋剂，包括哌甲酯（MPH）和甲基苯丙胺是常见的滥用药物，可以增强阿片类镇痛。然而，很少有研究已经解决了精神兴奋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，先前使用精神兴奋剂增加了对阿片类药物耐受性的发展，可能导致对阿片类镇痛药耐药的慢性疼痛患者数量增加。鉴于精神兴奋剂的广泛使用和滥用，这一人群长期遭受慢性疼痛的潜在痛苦和相关的医疗费用是巨大的。)

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. )