Psychostimulants induce long-term changes in nociception.

精神兴奋剂会引起伤害感受的长期变化。

基本信息

批准号：
8511595
负责人：
SUE A AICHER
金额：
$ 41.36万
依托单位：
WASHINGTON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8511595
关键词：
Absence of pain sensation Acute Acute Pain Address Adolescent Adult Attenuated Behavioral Cells Chronic Chronic inflammatory pain Clinical Data Development Dopamine Dopamine Antagonists Dopamine D1 Receptor Dopamine D2 Receptor Drug abuse Glutamates Health Health Care Costs Human Lead Life Link Long-Term Effects Mediating Methamphetamine Methylphenidate Microinjections Morphine Neuraxis Neurobiology Neurons Neurotransmitters Nociception Opioid Opioid Analgesics Opioid Receptor Output Pain Pathway interactions Patients Pharmaceutical Preparations Play Population Process Rattus Recording of previous events Resistance Role Science Signal Transduction Site System Talents Techniques Testing chronic pain desensitization dopamine system dopamine transporter dopaminergic neuron drug of abuse effective therapy experience inhibitor/antagonist methamphetamine abuse midbrain central gray substance mu opioid receptors novel pain inhibition presynaptic psychostimulant public health relevance receptor receptor sensitivity relating to nervous system research study response stimulant abuse young adult

项目摘要

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. )

描述（由申请人提供）：精神兴奋剂，例如哌甲酯（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良影响是众所周知的。尽管人们对长期影响知之甚少，但疼痛调节的变化似乎是一个潜在的重要后果。我们的初步数据表明，对幼龄大鼠长期给予 MPH 可增强吗啡的镇痛作用，并促进成年大鼠对吗啡耐受的发展。行为和解剖数据表明，多巴胺（精神兴奋剂作用的神经递质）和阿片类药物在导水管周围灰质（PAG）中相互作用。本提案中的研究重点关注 PAG 作为一种新型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。腹外侧 PAG 对于阿片类镇痛至关重要，并且还包含内在的多巴胺能神经元，这些神经元可能是精神兴奋药物的目标。因此，PAG 代表多巴胺和疼痛调节之间的汇聚部位。吗啡镇痛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。该提案采用协作团队科学方法在电生理、解剖和行为水平上检查 PAG 功能。目标#1 的实验将重点关注阿片类药物耐受性的变化，以及精神兴奋剂给药后阿片类药物受体的效力和脱敏。目标#2 中的实验将检验精神兴奋剂通过 PAG 神经处理的变化来增强慢性疼痛的假设。最后，目标 3 将检验以下假设：长期服用精神兴奋剂和慢性疼痛相结合将在 PAG 中的多巴胺和阿片类药物系统之间产生独特的相互作用。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长期影响的中央网络。我们将检验以下总体假设：PAG 是长期使用精神兴奋剂引起的伤害感受和镇痛变化的关键基础。拟议的研究将有助于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，从而开发出有效的治疗方法。）