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

痛苦-奖励的相互作用是复杂的。几项实验研究表明，范围广泛的愉快刺激对人类产生镇痛作用。最近，研究表明，停止疼痛刺激会在人类中产生愉快的反应。初步的功能性神经影像学研究表明，奖励诱导的镇痛与大脑奖励系统关键区域的激活和大脑疼痛基质区域的失活有关。相反，研究表明，疼痛刺激的中断不仅与疼痛网络活动的减少有关，而且还与大脑奖励系统活动的增加有关。在目前的提案中，我们将寻求证明内源性大麻素系统-介导大麻在大脑中的作用-是疼痛-奖励对抗过程的关键介质。内源性大麻素系统由脂质配体组成，主要结合两种大麻素受体CB1和CB2。重要的是，CB1受体高度集中在大脑奖励系统和疼痛基质的关键区域。在这里，我们将执行3个逻辑相关的实验。在项目的第一部分，我们将检查大麻素-1受体（CNR1）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”实验测量的影响。第一部分的目的是鉴定对疼痛-奖励对抗过程影响最大的CNR1基因多态性。在项目的第二部分，我们将使用功能磁共振成像（fMRI）扫描25名健康志愿者。在扫描仪中，受试者将执行功能磁共振成像（fMRI），以适应第一部分中管理的任务。第二部分的目标是描述在测量疼痛-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（例如连通性）。最后，在程序的第三部分，我们将扫描完成第一部分的50名参与者。受试者将根据CNR1基因多态性被分为两个亚组，在第一部分中，CNR1基因多态性与任务表现的关系最为密切。我们将招募携带与低和高CB1受体功能相关的基因型的参与者。在扫描仪中，参与者将执行第一部分中执行的任务的功能磁共振成像适应。该项目的第三个目标是证明CNR1基因型对两项任务中引发的大脑激活的影响。CNR1基因型对疼痛和奖励相关通路之间连通性的影响也将被研究。通过结合心理物理学、功能磁共振成像和行为遗传学，目前的提议将提供有关疼痛-奖励相互作用的神经化学和神经功能机制的重要信息。

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.