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Molecular mechanisms of placebo responses in humans.

Peciña M, Zubieta JK - Mol. Psychiatry (2014)

Bottom Line: Endogenous opioid and non-opioid mechanisms (for example, dopamine (DA), endocannabinoids (eCB)) have been implicated in the formation of placebo analgesic effects, with initial reports dating back three decades.As a consequence, the formation of biological placebo effects is now being linked to the concept of resiliency mechanisms, partially determined by genetic factors, and uncovered by the cognitive emotional integration of the expectations created by the therapeutic environment and its maintenance through learning mechanisms.The delineation of these processes within and across diseases would point to biological targets that have not been contemplated in traditional drug development.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry and Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI, USA.

ABSTRACT
Endogenous opioid and non-opioid mechanisms (for example, dopamine (DA), endocannabinoids (eCB)) have been implicated in the formation of placebo analgesic effects, with initial reports dating back three decades. Besides the perspective that placebo effects confound randomized clinical trials, the information so far acquired points to neurobiological systems that when activated by positive expectations and maintained through conditioning and reward learning are capable of inducing physiological changes that lead to the experience of analgesia and improvements in emotional state. Molecular neuroimaging techniques with positron emission tomography and the selective μ-opioid and D2/3 radiotracers [(11)C]carfentanil and [(11)C]raclopride have significantly contributed to our understanding of the neurobiological systems involved in the formation of placebo effects. This line of research has described neural and neurotransmitter networks implicated in placebo responses and provided the technical tools to examine inter-individual differences in the function of placebo-responsive mechanisms, and potential surrogates (biomarkers). As a consequence, the formation of biological placebo effects is now being linked to the concept of resiliency mechanisms, partially determined by genetic factors, and uncovered by the cognitive emotional integration of the expectations created by the therapeutic environment and its maintenance through learning mechanisms. Further work needs to extend this research into clinical conditions where the rates of placebo responses are high and its neurobiological mechanisms have been largely unexplored (for example, mood and anxiety disorders, persistent pain syndromes or even Parkinson disease and multiple sclerosis). The delineation of these processes within and across diseases would point to biological targets that have not been contemplated in traditional drug development.

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Personality traits effect on placebo-induced activation of regional μ-opioid receptor mediated neurotransmissionLeft: Regions of greater μ-opioid system activation during placebo administration in subjects with high levels of Ego Resilience, Straightforwardness and Altruism and low levels of Angry Hostility. Upper right: Upper right: x-scores correlations with μ-opioid system activation (change in μ-opioid BPND) in the NAc after placebo administration. Lower right: reductions in cortisol plasma levels (mg/dl) after placebo administration. The sustained pain challenge was administered during 20 min, starting at 45 min scan time. Abbreviations: aINS: Anterior Insula; NAc: nucleus accumbens; d/sgACC: dorsal and subgenual anterior cingulate cortex.
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Figure 1: Personality traits effect on placebo-induced activation of regional μ-opioid receptor mediated neurotransmissionLeft: Regions of greater μ-opioid system activation during placebo administration in subjects with high levels of Ego Resilience, Straightforwardness and Altruism and low levels of Angry Hostility. Upper right: Upper right: x-scores correlations with μ-opioid system activation (change in μ-opioid BPND) in the NAc after placebo administration. Lower right: reductions in cortisol plasma levels (mg/dl) after placebo administration. The sustained pain challenge was administered during 20 min, starting at 45 min scan time. Abbreviations: aINS: Anterior Insula; NAc: nucleus accumbens; d/sgACC: dorsal and subgenual anterior cingulate cortex.

Mentions: The role of opioid neurotransmission in the neurobiology of personality traits that might predict placebo effects has also been the focus of recent research. Given the role of μ-opioid receptor mediated neurotransmission in the maintenance of homeostasis during various forms of stress, including sustained pain43, personality traits such stress resiliency are likely to be mediated by opioid neurotransmission and potentially likely to explain inter-individual variability in placebo responses. In fact, new evidence suggest that personality traits related to stress resiliency and interpersonal relationships have a substantial impact on the capacity to develop placebo effects and could be employed to reduce variability in treatment trials where placebo effects can be particularly prominent and obscure the effects of potentially active treatments (for a review44). One study has examined the predictive value of scales assessing emotional, psychological, and social well-being, dispositional optimism, satisfaction with life and ego-resiliency on μ-opioid mediated placebo analgesia45. This study also evaluated overall personality traits (NEO Personality Inventory Revised46) and traits specifically related to the trait anxiety and reward processing. In this study Ego-Resiliency, Altruism, Straightforwardness (positive predictors) and Angry Hostility (negative predictor) accounted for 25% of the variation in placebo analgesic responses and had a predictive ability of 18%. Subjects scoring higher in these trait measures also presented greater placebo-induced activation of μ-opioid neurotransmission in the sg/dACC, OFC, INS, NAC, AMY and PAG (Figure 1). Additionally, they found significant reductions in cortisol plasma levels during placebo administration, which were correlated with reductions in subjective pain report and μ-opioid system activation in the dorsal ACC and PAG.


Molecular mechanisms of placebo responses in humans.

Peciña M, Zubieta JK - Mol. Psychiatry (2014)

Personality traits effect on placebo-induced activation of regional μ-opioid receptor mediated neurotransmissionLeft: Regions of greater μ-opioid system activation during placebo administration in subjects with high levels of Ego Resilience, Straightforwardness and Altruism and low levels of Angry Hostility. Upper right: Upper right: x-scores correlations with μ-opioid system activation (change in μ-opioid BPND) in the NAc after placebo administration. Lower right: reductions in cortisol plasma levels (mg/dl) after placebo administration. The sustained pain challenge was administered during 20 min, starting at 45 min scan time. Abbreviations: aINS: Anterior Insula; NAc: nucleus accumbens; d/sgACC: dorsal and subgenual anterior cingulate cortex.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4372496&req=5

Figure 1: Personality traits effect on placebo-induced activation of regional μ-opioid receptor mediated neurotransmissionLeft: Regions of greater μ-opioid system activation during placebo administration in subjects with high levels of Ego Resilience, Straightforwardness and Altruism and low levels of Angry Hostility. Upper right: Upper right: x-scores correlations with μ-opioid system activation (change in μ-opioid BPND) in the NAc after placebo administration. Lower right: reductions in cortisol plasma levels (mg/dl) after placebo administration. The sustained pain challenge was administered during 20 min, starting at 45 min scan time. Abbreviations: aINS: Anterior Insula; NAc: nucleus accumbens; d/sgACC: dorsal and subgenual anterior cingulate cortex.
Mentions: The role of opioid neurotransmission in the neurobiology of personality traits that might predict placebo effects has also been the focus of recent research. Given the role of μ-opioid receptor mediated neurotransmission in the maintenance of homeostasis during various forms of stress, including sustained pain43, personality traits such stress resiliency are likely to be mediated by opioid neurotransmission and potentially likely to explain inter-individual variability in placebo responses. In fact, new evidence suggest that personality traits related to stress resiliency and interpersonal relationships have a substantial impact on the capacity to develop placebo effects and could be employed to reduce variability in treatment trials where placebo effects can be particularly prominent and obscure the effects of potentially active treatments (for a review44). One study has examined the predictive value of scales assessing emotional, psychological, and social well-being, dispositional optimism, satisfaction with life and ego-resiliency on μ-opioid mediated placebo analgesia45. This study also evaluated overall personality traits (NEO Personality Inventory Revised46) and traits specifically related to the trait anxiety and reward processing. In this study Ego-Resiliency, Altruism, Straightforwardness (positive predictors) and Angry Hostility (negative predictor) accounted for 25% of the variation in placebo analgesic responses and had a predictive ability of 18%. Subjects scoring higher in these trait measures also presented greater placebo-induced activation of μ-opioid neurotransmission in the sg/dACC, OFC, INS, NAC, AMY and PAG (Figure 1). Additionally, they found significant reductions in cortisol plasma levels during placebo administration, which were correlated with reductions in subjective pain report and μ-opioid system activation in the dorsal ACC and PAG.

Bottom Line: Endogenous opioid and non-opioid mechanisms (for example, dopamine (DA), endocannabinoids (eCB)) have been implicated in the formation of placebo analgesic effects, with initial reports dating back three decades.As a consequence, the formation of biological placebo effects is now being linked to the concept of resiliency mechanisms, partially determined by genetic factors, and uncovered by the cognitive emotional integration of the expectations created by the therapeutic environment and its maintenance through learning mechanisms.The delineation of these processes within and across diseases would point to biological targets that have not been contemplated in traditional drug development.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry and Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI, USA.

ABSTRACT
Endogenous opioid and non-opioid mechanisms (for example, dopamine (DA), endocannabinoids (eCB)) have been implicated in the formation of placebo analgesic effects, with initial reports dating back three decades. Besides the perspective that placebo effects confound randomized clinical trials, the information so far acquired points to neurobiological systems that when activated by positive expectations and maintained through conditioning and reward learning are capable of inducing physiological changes that lead to the experience of analgesia and improvements in emotional state. Molecular neuroimaging techniques with positron emission tomography and the selective μ-opioid and D2/3 radiotracers [(11)C]carfentanil and [(11)C]raclopride have significantly contributed to our understanding of the neurobiological systems involved in the formation of placebo effects. This line of research has described neural and neurotransmitter networks implicated in placebo responses and provided the technical tools to examine inter-individual differences in the function of placebo-responsive mechanisms, and potential surrogates (biomarkers). As a consequence, the formation of biological placebo effects is now being linked to the concept of resiliency mechanisms, partially determined by genetic factors, and uncovered by the cognitive emotional integration of the expectations created by the therapeutic environment and its maintenance through learning mechanisms. Further work needs to extend this research into clinical conditions where the rates of placebo responses are high and its neurobiological mechanisms have been largely unexplored (for example, mood and anxiety disorders, persistent pain syndromes or even Parkinson disease and multiple sclerosis). The delineation of these processes within and across diseases would point to biological targets that have not been contemplated in traditional drug development.

Show MeSH
Related in: MedlinePlus