PET Imaging of Individual Differences in Regional Mu-Opioid Activation in Motivational Brain Circuitry.

Abstract

Humans show wide variation in susceptibility to diseases of chronic pain and addiction. A common underlying neurochemical circuitry of these diseases is the motivational circuitry of the brain, which comprises the basal ganglia, prefrontal cortex, and limbic structures. Understanding how individual differences such as genotype and sex affect this system in both healthy and addicted populations will advance our understanding of its basic mechanisms, how it becomes dysregulated, and what makes certain people susceptible to disease states. We conducted a series of studies using positron emission tomography (PET) that allowed us to examine individual differences in the neurochemical functioning of the motivational circuitry of the brain, using two experimental models to engage the system: placebo analgesia in healthy subjects and cigarette smoking in heavy smokers. In the first study, we examined sex differences in µ-opioid receptor related neurotransmission during placebo analgesia by measuring non-displaceable binding potential (BPND) with the radiotracer [11C] carfentanil. We found significant sex differences in regional changes in BPND across conditions of pain and pain with placebo administration, as well as across conditions of pain anticipation and pain with placebo anticipation. The regional differences were in structures throughout the overlapping pain-modulatory and motivational circuitry. In a second experiment using the same subjects and experimental design, the prior analyses were expanded to include an examination of the effect of the A118G polymorphism in the µ-opioid receptor on placebo analgesia and sex differences. There was a significant interaction between sex and genotype in regional changes in µ-opioid receptor BPND across conditions of pain/placebo and anticipation of pain/placebo. The third experiment measured significant changes in µ-opioid receptor and dopamine D2/D3 BPND in response to cigarette smoking in heavy smokers, and these regional changes were also associated with A118G genotype. These results indicate that motivational system function is affected by individual differences in genotype and sex, and that these factors could underlie susceptibility to disease states within the motivational system. Additionally, the results point to the fact that individual variation should be taken into account when designing studies of the motivational system to gain a more accurate picture of its function.