The neurobiology of placebo analgesia.

Placebo analgesia is a manipulation of cognitive expectancy whereby the subject's expectation of pain relief promotes diminished pain ratings. Endogenous opioids have been found to play a role in mediating this phenomenon, and advances in functional neuroimaging have allowed the in vivo examination of pain- and placebo-induced opioid neurotransmission in humans. The brain circuitry activated during placebo analgesia exhibits substantial overlap with that involved in motivation, suggesting that similar cognitive elements might be involved in the placebo effect. As such associations remain theoretical, this work employs positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) to test whether individual differences in placebo effects reflect differences in the function of underlying motivational circuitry. First, the feasibility of assessing changes in endogenous opioid and dopamine neurotransmission following a physiological challenge is demonstrated using PET with [11C]carfentanil and [11C]raclopride. A similar methodology is used to demonstrate a pro-nociceptive role for dopamine during sustained pain. This technique is then employed to detect activation of these systems in response to pain, and then during pain with a placebo intervention. These experiments reveal that placebos activate ventral striatal dopamine and endogenous opioid neurotransmission throughout the brain, that this activation is coordinated, and is positively related to the subjective experience of the placebo. Placebo-induced dopamine neurotransmission during the anticipation of pain is also found to be related to expectations and counterfactual comparisons related to the placebo intervention. This anticipatory activity is generalizable to other forms of reward responding, such that the ventral basal ganglia is similarly activated by anticipating a placebo or a monetary reward, as measured with fMRI. Further, the response magnitude to the placebo and monetary reward were correlated, suggesting that both mechanisms demonstrate an intrinsic interindividual variability. Finally, pharmacological blockade of endogenous opioid neurotransmission is found to result in dysfunctional activation of synaptic activity involved in reward processing. These experiments suggest that placebo analgesia reflects a context-specific activation of underlying motivational circuitry that is relatively consistent between contexts. These findings serve to account for and predict individual differences in placebo responses, with implications for future experiments, as well as for clinical trials.Ph.D.Biological SciencesNeurosciencesUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/126816/2/3276289.pd