Neurobiological Mechanisms of Placebo Responses

Abstract

Expectations, positive or negative, are modulating factors influencing behavior. They are also thought to underlie placebo effects, potentially impacting perceptions and biological processes. We used sustained pain as a model to determine the neural mechanisms underlying placebo-induced analgesia and affective changes in healthy humans. Subjects were informed that they could receive either an active agent or an inactive compound, similar to routine clinical trials. Using PET and the mu-opioid selective radiotracer [(11)C]carfentanil we demonstrate placebo-induced activation of opioid neurotransmission in a number of brain regions. These include the rostral anterior cingulate, orbitofrontal and dorsolateral prefrontal cortex, anterior and posterior insula, nucleus accumbens, amygdala, thalamus, hypothalamus, and periaqueductal grey. Some of these regions overlap with those involved in pain and affective regulation but also motivated behavior. The activation of endogenous opioid neurotransmission was further associated with reductions in pain report and negative affective state. Additional studies with the radiotracer [(11)C]raclopride, studies labeling dopamine D2/3 receptors, also demonstrate the activation of nucleus accumbens dopamine during placebo administration under expectation of analgesia. Both dopamine and opioid neurotransmission were related to expectations of analgesia and deviations from those initial expectations. When the activity of the nucleus accumbens was probed with fMRI using a monetary reward expectation paradigm, its activation was correlated with both dopamine, opioid responses to placebo in this region and the formation of placebo analgesia. These data confirm that specific neural circuits and neurotransmitter systems respond to the expectation of benefit during placebo administration, inducing measurable physiological changes.

“Dirty electricity”: what, where, and should we care?

“…Generally, this tends to increase treatment effects compared to blinded studies (Schulz et al, 1995;Day and Altman, 2000), and is especially problematic in these studies where the cases were self-reported EHS patients. Studies have shown that placebo or nocebo effects can modulate perception and biological processes inducing measurable physiological changes (Enck et al, 2008;Zubieta and Stohler, 2009), and indeed changes in blood glucose levels in these studies can alternatively plausibly be ascribed to expectation and anxiety (Surwit et al, 1992;Surwit and Schneider, 1993;Park et al, 2008) rather than to the reduction in exposure. Furthermore, both exposure and biological response are self reported and have been measured at random moments throughout the day.…”

Placebo-mediated, Naloxone-sensitive suggestibility of short-term memory performance

“…Obvious candidates include the ventral striatum, the amygdala, the insular and anterior cingular cortices and possibly other structures where the opioid system interacts with dopaminergic neurotransmission (e.g. Zubieta & Stohler, 2009). The interactions may operate via influences on valence processing and/ or more directly on (working-) memory-related pathways Several potential confounders were considered in this study, including (1) stress, (2) drug-induced emotional blurring and (3) unspecific drug-related cognitive effects potentially affecting attention.…”

“…Within the field of placebo research, endogenous opioids were the first neurobiological substrates consistently enlisted as a physiological mediator of the placebo effect -when the administration of the opioid-antagonist Naloxone was shown to reduce placebo-mediated analgesia (Levine, Gordon, and Fields, 1978). Since then, placebo research has expanded enormously and opioids continue to play a prominent role (Price, Finniss, and Benedetti, 2008;Zubieta and Stohler, 2009). For example, brain-imaging studies have begun to specify the role of opioids in placebo processes by localizing placebo-induced functional changes in opioid-signalling in the brain (Zubieta, Bueller, Jackson, Scott, Xu, Koeppe, Nichols, and Stohler, 2005).…”

Migraine and Reward System—Or Is It Aversive?

“…Dopamine release within the nucleus accumbens occurs following alleviation of ongoing pain, or the expectation of pain relief [30]. However, direct evidence for modulation of dopamine in the nucleus accumbens by aversive stimuli has been demonstrated.…”