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

痛苦和回报之间的相互作用是复杂的。一些实验研究表明，各种令人愉悦的刺激对人类都有止痛作用。最近，有研究表明，停止疼痛刺激会在人类身上产生愉快的反应。初步的功能神经成像研究表明，奖赏诱导的镇痛与大脑奖赏系统的关键区域的激活和疼痛基质的大脑区域的失活有关。相反，研究表明，疼痛刺激的中断不仅与疼痛网络中的活动减少有关，还与大脑奖励系统中的活动增加有关。在目前的提案中，我们将试图证明，内源性大麻素系统--它在大脑中调节大麻的影响--是疼痛-回报对抗过程的关键中介。内源性大麻素系统由脂类配体组成，主要与两种大麻素受体CB1和CB2结合。重要的是，CB1受体高度集中在大脑奖赏系统和疼痛矩阵的关键区域。在这里，我们将执行3组逻辑上相关的广泛实验。在该计划的第一部分，我们将检查大麻素-1受体(CNR1)基因多态性对200名健康志愿者进行的“奖赏诱导止痛”和“止痛愉悦”实验措施的影响。第一部分的目的是确定CNR1基因的多态对痛-报偿拮抗过程的影响最大。在计划的第二部分，我们将使用功能磁共振成像(FMRI)对25名健康志愿者进行扫描。在扫描仪中，受试者将对第一部分中实施的任务进行fMRI调整。第二部分的目标是描述在测量疼痛-回报对手过程的任务中，与疼痛和回报相关的激活之间的相互作用(例如连通性)。最后，在计划的第三部分，我们将扫描50名完成第一部分的参与者。受试者将根据第一部分中出现的与任务表现最密切相关的CNR1基因多态被分成两个小组。我们将招募携带与CB1受体功能低和高相关的基因类型的参与者。在扫描仪中，参与者将对第一部分中执行的任务进行fMRI调整。该计划的第三个目标是展示CNR1基因类型对两个任务中引发的大脑激活的影响。CNR1基因分型对疼痛和回报相关通路之间的连通性的影响也将被检测。通过结合心理物理学、功能磁共振成像和行为遗传学，目前的提议将提供涉及疼痛-回报相互作用的神经化学和神经功能机制的关键信息。

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.