Psychostimulants induce long-term changes in nociception.

精神兴奋剂会引起伤害感受的长期变化。

• 批准号: 8306235
• 负责人: SUE A AICHER
• 金额: $ 44.69万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8306235
• 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

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. )

描述（由申请人提供）：广泛使用和滥用的精神刺激剂，例如甲化酯（MPH）和甲基苯丙胺。众所周知，甲基苯丙胺滥用的短期不良健康影响。尽管对长期影响知之甚少，但疼痛调节的变化似乎是潜在的重要结果。我们的初步数据表明，长期对年轻大鼠的MPH施用会增强吗啡抗伤害感受，并促进成年人对吗啡的耐受性的发展。行为和解剖学数据表明，多巴胺，精神刺激剂作用的基础神经递质和阿片类药物在周围灰色（PAG）中相互作用。该提案中的研究集中在PAG上，是一种新型的共享神经生物学底物，介导了与精神刺激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，还包含固有的多巴胺能神经元，这可能是精神刺激药物的靶标。因此，PAG代表多巴胺和疼痛调节之间的收敛位点。吗啡抗伤害感受和耐受性的变化可能是由于阿片类药物效力的变化或基础疼痛状态的变化引起的。该建议使用协作团队科学方法来检查电生理，解剖学和行为水平的PAG功能。 AIM＃1中的实验将集中于阿片类药物耐受性的变化，以及精神刺激施用后阿片类药物的效力和脱敏。 AIM＃2中的实验将检验以下假设：心理刺激剂通过PAG中神经加工的变化增强了慢性疼痛。最后，AIM＃3将检验以下假设：将慢性精神刺激剂和慢性疼痛结合起来将在PAG中产生多巴胺和阿片类药物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，以及这些细胞如何适合中心网络，这些网络是药物滥用对疼痛的长期后果的基础。我们将测试总体假设，即PAG是慢性精神刺激使用产生的伤​​害感受和镇痛变化的关键底物。拟议的研究将更好地了解有助于药物滥用史的患者慢性疼痛的细胞机制，因此可以开发有效的治疗方法。 ） 公共卫生相关性：包括甲化酯（MPH）和甲基苯丙胺在内的精神刺激剂是通常滥用的药物，可以增强阿片类镇痛。但是，很少有研究解决了心理刺激使用和滥用内源性疼痛途径的长期后果。我们的初步数据表明，先前的精神刺激使用会增加对阿片类药物的耐受性的发展，这可能导致慢性疼痛患者对阿片类镇痛药的耐药性增加。鉴于对精神刺激剂的广泛使用和滥用，该人群中慢性疼痛和相关医疗费用的长期痛苦是巨大的。 ）