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

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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.