The endogenous cannabinoid system is involved in pain-reward opponent mechanisms

疼痛-奖励的相互作用是复杂的。一些实验研究表明，大范围的愉快刺激对人类产生镇痛作用。最近，已经表明，停止疼痛刺激会在人类中产生愉快的反应。初步的功能性神经成像研究表明，奖励诱导的镇痛与大脑奖励系统的关键区域的激活和疼痛矩阵的大脑区域的去激活有关。相反，已经表明疼痛刺激的中断不仅与疼痛网络的活动减少有关，而且与大脑奖励系统的活动增加有关。在目前的提案中，我们将试图证明内源性大麻素系统-介导大麻在大脑中的作用-是疼痛奖励对手过程的关键介导者。内源性大麻素系统由主要与两种大麻素受体CB 1和CB 2结合的脂质配体组成。重要的是，CB 1受体高度集中在大脑奖励系统和疼痛矩阵的关键区域。在这里，我们将进行3个逻辑相关的广泛实验。在该计划的第一部分，我们将研究大麻素-1受体（CNR 1）基因多态性对200名健康志愿者的“奖励诱导镇痛”和“疼痛缓解愉悦”实验措施的影响。第1部分的目的是确定CNR 1基因多态性发挥最强的影响疼痛奖励对手的过程。在该计划的第二部分，我们将使用功能性磁共振成像（fMRI）扫描25名健康志愿者。在扫描仪中，受试者将执行第1部分中管理的任务的fMRI适应。第2部分的目的是描述在测量疼痛-奖励对手过程的任务中疼痛和奖励相关激活之间的相互作用（例如连接性）。最后，在程序的第三部分，我们将扫描50名完成第1部分的参与者。受试者将根据CNR 1基因多态性分为两个亚组，该基因多态性在第1部分中与任务表现最密切相关。我们将招募携带与低和高CB 1受体功能相关的基因型的参与者。在扫描仪中，参与者将执行第1部分中执行的任务的fMRI适应。该计划的第三个目标是证明CNR 1基因型对两项任务中引起的大脑激活的影响。CNR 1基因型对疼痛和奖励相关通路之间的连接的影响也将被检查。通过结合心理物理学，功能磁共振成像和行为遗传学，目前的建议将提供关键信息的神经化学和神经功能机制参与疼痛奖励的相互作用。

Pain-reward interactions are complex. Several experimental studies have shown that a wide range of pleasant stimuli produce analgesic effects in humans. More recently, it has been shown that the cessation of pain stimulation produces pleasant responses in humans. Preliminary functional neuro-imaging studies have shown that reward-induced analgesia is associated with the activation of key regions of the brain reward system and de-activation of brain regions of the pain matrix. Conversely, it has been shown that the interruption of pain stimulation is not only associated with reduced activity in pain networks, but also increased activity in the brain reward system. In the current proposal, we will seek to show that the endogenous cannabinoid system - which mediates the effects of cannabis in the brain - is a key mediator of pain-reward opponent processes. The endogenous cannabinoid system is composed of lipid ligands which mainly bind to two cannabinoid receptors, CB1 and CB2. Importantly, CB1 receptors are highly concentrated in the brain reward system and in key regions of the pain matrix. Here, we will perform 3 logically related broad sets of experiments. In the first part of the program, we will examine the influence of cannabininoid-1 receptor (CNR1) gene polymorphisms on experimental measures of “reward-induced analgesia” and “pain relief pleasantness” administered to 200 healthy volunteers. The objective of Part 1 is to identify the CNR1 gene polymorphism exerting the strongest influence on pain-reward opponent processes. In the second part of the program, we will scan 25 healthy volunteers using functional magnetic resonance imaging (fMRI). In the scanner, subjects will perform fMRI adaptations of the tasks administered in Part 1. The objective of Part 2 is to characterize the interactions (e.g. connectivity) between pain- and reward-related activations during tasks measuring pain-reward opponent processes. Finally, in the third part of the program, we will scan 50 participants having completed Part 1. Subjects will be divided in two sub-groups based on the CNR1 gene polymorphism emerging as being the most closely associated with task performance in Part1. We will recruit participants carrying the genotypes associated with low and high CB1 receptor functioning. In the scanner, participants will perform fMRI adaptations of the tasks performed in Part 1. The third objective of the program is to demonstrate the influence of CNR1 genotypes on brain activations elicited during both tasks. The influence of CNR1 genotypes on the connectivity between pain- and reward-related pathways will also be examined. By combining psychophysics, fMRI and behavioral genetics, the current proposal will provide crucial information on the neuro-chemical and neuro-functional mechanisms involved in pain-reward interactions.