To many clinicians and researchers, the evidence for psychological factors influencing the treatment response may seem unconvincing without knowledge of the physiological mechanisms by which these effects can manifest. Here, we review the neural circuitry in the brain for which there is currently the strongest evidence for a mediating role in placebo analgesia.
Evidence has been mounting over the past 30 years for a central role of descending pain modulatory circuits, notably the endogenous opioid system, in mediating placebo analgesic responses. The endogenous descending pain modulatory circuit consists of the midbrain peri-aqueductal grey (PAG), the rostral ventral medulla (RVM), and the spinal cord [31
]. The PAG integrates input from the limbic forebrain (including the amygdala and pregenual cingulate cortex) and the diencephalon with ascending input from the dorsal horn [30
]. Early studies described the PAG-RVM system as a descending inhibitory control that plays a role in endogenous analgesia or in creating sufficient spinal gain for pain sensory signal detection. It is now clear that the descending control is bi-directional and includes facilitatory mechanisms [32
]. The final output of this system is determined by the dynamic balance between inhibition and facilitation which can be altered in different behavioral, emotional, and pathological states. Two of the candidate neuromodulatory systems are the endogenous opioid and serotonin (5-hydroxytryptamine, or 5-HT) systems.
Until now, much of the evidence for the role of endogenous opioids and 5-HT in the modulation of pain processing has arisen mainly from animal experiments. These studies suggest that the serotonergic system works together with the opioid system to mediate a nociceptive gateway within the central nervous system via a descending network of serotonergic spinal-raphe projections [33
]. The actions of pain transmission are further mediated via serotonergic projections to the spinal dorsal horn from brain regions such as the pregenual cingulate cortex, thalamus, hypothalamus, PAG, RVM, and raphe magnus [33
In humans, neuroimaging has provided evidence that the endogenous opioid system is central to mediating placebo effects on pain [37
]. These studies provide evidence that placebo analgesia is associated with activation of the endogenous opioid system and with μ-opioid receptors within a number of brain regions, including prefrontal, limbic, and brainstem regions. Furthermore, the changes in activity in these brain regions are related to reductions in the physical and emotional aspects of the pain experience, indicating that variation in endogenous opioid transmission relates to variances in placebo effects across individuals. A recent functional magnetic resonance imaging (fMRI) study has shown activity within all key regions of the descending pain modulatory system - rostral anterior cingulate cortex (rACC), hypothalamus, PAG, and RVM - during placebo analgesia, and this activity was significantly decreased when the μ-opioid receptor antagonist naloxone was present during the placebo intervention [40
]. Coupling between rACC and PAG was significantly increased during placebo analgesia but in the presence of naloxone was not different versus control. Positron emission tomography imaging has also been used to determine the regional activation of endogenous opioid neurotransmission during placebo analgesia [41
]. Expectation-induced placebo analgesia was associated with marked activation of μ-opioid receptor-mediated neurotransmission in an extensive set of brain regions [41
], including anterior cingulate cortex. Furthermore, opioid-related activities in several brain regions within this network correlated with changes in specific self-report measures of placebo analgesia, such as pain intensity and unpleasantness, as well as subjects' emotional states.
Despite the above advances in our understanding of the physiological mechanisms of placebo analgesia, there are significant gaps in our knowledge. While there is evidence that a network of brain regions is involved in placebo analgesia (including prefrontal, cingulate, orbito-frontal, limbic, and brainstem regions) and that responses in these brain regions are substantially driven by changes in expectation [42
], it is not known precisely where in the brain expectations are generated and maintained or by what mechanism these expectations come to act on the descending pain modulatory circuit, including the endogenous opioid system. Although the prefrontal cortices play an important role in mediating placebo analgesia, there is little evidence outside of the placebo literature for their role in expectation effects on pain. One possible explanation is that the prefrontal cortices are not involved in the expression of expectation but rather in their generation through processes of conditioning and learning. fMRI studies have identified a common prefrontal cortical network that is involved in conditioned placebo analgesia [43
] and that consists of areas that are also important in memory and recall.
Further gaps in our knowledge of the mechanisms of placebo are in relation to the role of neurotransmitter systems other than opioids. Because of its central role in the central modulation of pain processing, the 5-HT neurotransmitter system is one candidate, and there is emerging evidence for a role of this system in placebo response. Carriers of the S allele of the 5-HT transporter (5-HTT) gene have been linked with a range of anxiety-related personality traits, such as self-reported neuroticism and agreeableness [45
]. Furmark and colleagues [48
] found an association between the human genes responsible for driving serotonergic activation of the amygdala during social anxiety and placebo-induced reductions in stress. It is currently not known whether this anxiety-related amygdala sensitivity would have an impact on placebo analgesic responses.
There is also interest in further understanding the possible role of the principal stress response pathway, the hypothalamic-pituitary-adrenal (HPA) axis, in placebo response. The HPA axis has a close relationship to negative psychological states such as anticipatory anxiety [49
]. Although little evidence links the HPA axis with the placebo response, its activation has been linked to the nocebo response. Benedetti and colleagues [50
] showed that administration of an inert substance coupled with a negative verbal suggestion upregulates the HPA axis. It is unclear whether placebo and nocebo treatments would have opposing effects on the HPA axis. In rodents, endogenous opioids have been shown to exert both inhibitory and facilitatory effects on HPA activity. One pathway for this inhibition is an effect on cortisol, which is both a product and an inhibitor of the HPA axis. Morphine, for example, was shown to activate adrenocortical release indirectly via the hypothalamus and anterior pituitary and directly via the adrenal gland. In humans, however, endogenous opioids predominantly inhibit HPA axis activity, whereas high doses of the opioid receptor antagonist, naloxone, activate the HPA axis. these findings suggest a possible interaction between the opioid system and HPA axis as part of the placebo response, and opioid release inhibits stress response pathways. Although currently there is lack of direct evidence to support this hypothesis, the association of placebo response and reductions in anxiety makes this an important area for future study.