Interaction of Smoking and Chronic Pain at Neurochemical and Phenotypic Levels

描述（由申请方提供）：在尼古丁依赖和持续性疼痛状况之间观察到高水平的合并症。也有建议认为，尼古丁依赖可能会使经历持续性疼痛的患者的表现和结果复杂化，这种疼痛已经是一种既难以治疗又可能自我延续的病症。实验证据表明，尼古丁对疼痛调节机制有影响。然而，尼古丁依赖和慢性疼痛之间的相互作用的影响在神经生物学和表型水平上都知之甚少，特别是在人类中。本建议关注慢性疼痛和尼古丁依赖的病理生理学中涉及的神经化学机制的功能的个体差异，以及它们如何影响这两种疾病的个体特征。建议检查内源性阿片样物质和多巴胺神经传递的功能，这些系统参与CNS中尼古丁的强化作用，但也已知在慢性疼痛状况中失调。我们建议首先描述尼古丁依赖对多巴胺和阿片系统对持续实验性疼痛的反应的影响，将其与非吸烟者对照组进行比较。然后，神经生物学反应将与疼痛心理物理学和与尼古丁依赖相关的测量（例如，渴望）。在慢性腰痛患者、尼古丁依赖者或非吸烟者的样本中提出了类似的研究和分析。我们将采用选择性放射性示踪剂[11 C]卡芬太尼和[11 C]雷氯必利和正电子发射断层扫描法对多巴胺D2/3和5-阿片受体进行无创定量。将对基线、疼痛预期和疼痛反应进行量化，并根据拟定的四个匹配志愿者组的心理物理特征进行检查：非吸烟者和尼古丁依赖对照组、慢性腰痛非吸烟者和尼古丁依赖组。在这些研究完成后，我们将能够确定尼古丁依赖如何改变人类的疼痛反应，以及临床和实验疼痛如何改变这种成瘾的神经生物学和表型元素（例如，渴望）。此外，将在神经功能水平上检查现有持续性疼痛状况与尼古丁依赖之间的相互作用，并与个体临床和实验性疼痛体验以及尼古丁依赖性指标相关。尼古丁依赖和慢性疼痛都是具有高并发症的自我延续性疾病。建议的研究将澄清他们的点在神经生物学和心理物理水平的相互作用，提供了非常需要的信息，为理解患者的表现和临床课程的个体差异。这些信息最终将通过为他们的发展提供神经生物学框架来指导个性化的治疗策略。 公共卫生相关性：慢性腰痛和尼古丁成瘾是常见的并发症。这些研究将确定尼古丁依赖、持续性腰痛及其对大脑神经递质系统的相互作用的影响，这些神经递质系统参与尼古丁的强化作用和疼痛调节。然后，神经反应将与个体疼痛报告和尼古丁成瘾的严重程度相关。

DESCRIPTION (provided by applicant): High levels of comorbidity have been observed between nicotine dependence and persistent pain conditions. There are also suggestions that nicotine dependence may complicate the presentation and outcomes of patients experiencing persistent pain, already a condition that is both difficult to treat and can be self- perpetuating. Experimental evidence shows that nicotine has effects on pain regulatory mechanisms. The effects of the interaction between nicotine dependence and chronic pain are however poorly understood at both neurobiological and phenotypic levels, particularly in humans. The present proposal is concerned with individual variations in the function of neurochemical mechanisms implicated in the pathophysiology of both chronic pain and nicotine dependence and how they impact on the individual characteristics of both disorders. It is proposed to examine the function of endogenous opioid and dopamine neurotransmission, systems involved in the reinforcing effects of nicotine in the CNS, but also known to be dysregulated in chronic pain conditions. We propose to first characterize the effects of nicotine dependence on the responses of dopamine and opioid systems to sustained experimental pain, by comparing them to those of non-smoker controls. Neurobiological responses will then be related to pain psychophysics and measures related to nicotine dependence (e.g., craving). Similar studies and analyses are proposed in samples of chronic low back pain patients, nicotine dependent or non-smokers. We will employ the selective radiotracers [11C]carfentanil and [11C]raclopride and positron emission tomography for the non-invasive quantification of dopamine D2/3 and 5- opioid receptors. Baseline, pain expectation and pain responses will be quantified and examined against psychophysical characteristics across the four matched volunteer groups proposed: non-smoker and nicotine dependent controls, chronic low back pain non-smokers and nicotine dependent. At the completion of these studies we will be able to determine how nicotine dependence modifies pain responses in humans, and how pain, both clinical and experimental, modifies neurobiological and phenotypic elements of this addiction (e.g., craving). In addition, the interaction between an existing persistent painful condition and nicotine dependence will be examined at the neural function level and related to the individual clinical and experimental pain experience and measures of nicotine dependence. Both nicotine dependence and chronic pain are self- perpetuating conditions with high comorbidity. The studies proposed will clarify their points of interaction at neurobiological and psychophysical levels, providing much needed information for the understanding of individual variations in patient presentation and clinical courses. This information would ultimately guide individualized treatment strategies by providing a neurobiological framework for their development. PUBLIC HEALTH RELEVANCE: Chronic low back pain and nicotine addiction are frequent co-occurring conditions. These studies will determine the effect of nicotine dependence, persistent low back pain and their interaction on brain neurotransmitter systems that are involved in both the reinforcing effects of nicotine and pain regulation. Neural responses will then be related to the individual pain report and severity of nicotine addiction.