Psychostimulants induce long-term changes in nociception.

描述（由申请人提供）：精神兴奋剂，如哌甲酯（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利影响是众所周知的。尽管对其长期影响知之甚少，但疼痛调节的改变似乎是一个潜在的重要后果。我们的初步数据表明，长期给予幼鼠MPH可以增强吗啡的抗痛觉作用，并促进成年鼠对吗啡的耐受性。行为学和解剖学数据表明，多巴胺（精神兴奋剂作用的神经递质）和阿片样物质在导水管周围灰质（PAG）中相互作用。本研究的重点是PAG作为一种新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节变化。腹侧PAG对阿片镇痛至关重要，也含有可能成为精神兴奋剂药物靶点的内在多巴胺能神经元。因此，PAG代表了多巴胺和疼痛调节之间的一个交汇点。吗啡抗痛觉和耐受性的变化可能是由阿片类药物效力的变化或基础疼痛状态的变化引起的。本研究采用团队协作的科学方法，从电生理、解剖学和行为学的层面研究PAG的功能。Aim #1的实验将集中于阿片耐受性的变化，以及阿片受体的效力和给药后的脱敏。Aim #2的实验将验证精神兴奋剂通过改变PAG的神经处理来增强慢性疼痛的假设。最后，Aim #3将测试慢性精神兴奋剂和慢性疼痛联合使用将在PAG中产生多巴胺和阿片系统之间产生独特的相互作用的假设。这些研究将阐明PAG中阿片/多巴胺相互作用的细胞底物，以及这些细胞如何适应药物滥用对疼痛的长期影响的中枢网络。我们将检验PAG是慢性精神兴奋剂使用所产生的伤害和镇痛变化的关键底物的整体假设。拟议的研究将提供一个更好的理解细胞机制，促进慢性疼痛患者的药物滥用史，从而可以开发有效的治疗方法。)

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. )