Wager TD, Scott DJ, Zubieta JK. Placebo effects on human mu-opioid activity during pain. Proc Natl Acad Sci USA 104: 11056-11061

Department of Psychology, Columbia University, 1190 Amsterdam Avenue, New York, NY 10027, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 07/2007; 104(26):11056-61. DOI: 10.1073/pnas.0702413104
Source: PubMed


Placebo-induced expectancies have been shown to decrease pain in a manner reversible by opioid antagonists, but little is known about the central brain mechanisms of opioid release during placebo treatment. This study examined placebo effects in pain by using positron-emission tomography with [(11)C]carfentanil, which measures regional mu-opioid receptor availability in vivo. Noxious thermal stimulation was applied at the same temperature for placebo and control conditions. Placebo treatment affected endogenous opioid activity in a number of predicted mu-opioid receptor-rich regions that play central roles in pain and affect, including periaqueductal gray and nearby dorsal raphe and nucleus cuneiformis, amygdala, orbitofrontal cortex, insula, rostral anterior cingulate, and lateral prefrontal cortex. These regions appeared to be subdivided into two sets, one showing placebo-induced opioid activation specific to noxious heat and the other showing placebo-induced opioid reduction during warm stimulation in anticipation of pain. These findings suggest that a mechanism of placebo analgesia is the potentiation of endogenous opioid responses to noxious stimuli. Opioid activity in many of these regions was correlated with placebo effects in reported pain. Connectivity analyses on individual differences in endogenous opioid system activity revealed that placebo treatment increased functional connectivity between the periaqueductal gray and rostral anterior cingulate, as hypothesized a priori, and also increased connectivity among a number of limbic and prefrontal regions, suggesting increased functional integration of opioid responses. Overall, the results suggest that endogenous opioid release in core affective brain regions is an integral part of the mechanism whereby expectancies regulate affective and nociceptive circuits.

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    • "We note however that permutation testing is mandatory to obtain accurate p-values in many settings (family-wise error control, cluster-size tests, TFCE test); see e.g. Wager et al. (2007). For such cases, SVR might be worth considering. "
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    ABSTRACT: Multi-subject datasets used in neuroimaging group studies have a complex structure, as they exhibit non-stationary statistical properties across regions and display various artifacts. While studies with small sample sizes can rarely be shown to deviate from standard hypotheses (such as the normality of the residuals) due to the poor sensitivity of normality tests with low degrees of freedom, large-scale studies (e.g. >100 subjects) exhibit more obvious deviations from these hypotheses and call for more refined models for statistical inference. Here, we demonstrate the benefits of robust regression as a tool for analyzing large neuroimaging cohorts. First, we use an analytic test based on robust parameter estimates; based on simulations, this procedure is shown to provide an accurate statistical control without resorting to permutations. Second, we show that robust regression yields more detections than standard algorithms using as an example an imaging genetics study with 392 subjects. Third, we show that robust regression can avoid false positives in a large-scale analysis of brain-behavior relationships with over 1,500 subjects. Finally we embed robust regression in the Randomized Parcellation Based Inference (RPBI) method and demonstrate that this combination further improves the sensitivity of tests carried out across the whole brain. Altogether, our results show that robust procedures provide important advantages in large-scale neuroimaging group studies. Copyright © 2015. Published by Elsevier Inc.
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    • "Identifying the cell types releasing various types of endogenous opioids was not examined. The mass dose used in this study is in a common range (20–30 pg/kg) for human PET studies with [ 11 C]carfentanil (Colasanti et al., 2012; Ray et al., 2011; Wager et al., 2007; Wand et al., 2011). The dose of [ 11 C]carfentanil is less than 15% of the therapeutic dose for conscious sedation (Cortinez Table 2B Power analyses for OPRM1 A118G differences on decreases in endogenous mu opioid release. "
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    ABSTRACT: To determine if overnight tobacco abstinent carriers of the AG or GG (*G) vs. the AA variant of the human mu opioid receptor (OPRM1) A118G polymorphism (rs1799971) differ in [(11)C]carfentanil binding after tobacco smoking. Twenty healthy American male smokers who abstained from tobacco overnight were genotyped and completed positron emission tomography (PET) scans with the mu opioid receptor agonist, [(11)C]carfentanil. They smoked deniconized (denic) and average nicotine (avnic) cigarettes during the PET scans. Smoking avnic cigarette decreased the binding potential (BPND) of [(11)C]carfentanil in the right medial prefrontal cortex (mPfc; 6,56,18), left anterior medial prefrontal cortex (amPfc; -2,46,44), right ventral striatum (vStr; 16, 3, -10), left insula (Ins; -42,10,-12), right hippocampus (Hippo; 18,-6,-14) and left cerebellum (Cbl; -10,-88,-34), and increased the BPND in left amygdala (Amy; -20,0,-22), left putamen (Put; -22, 10,-6) and left nucleus accumbens (NAcc; -10,12,-8). In the AA allele carriers, avnic cigarette smoking significantly changed the BPND compared to after denic smoking in most brain areas listed above. However in the *G carriers the significant BPND changes were confirmed in only amPfc and vStr. Free mu opioid receptor availability was significantly less in the *G than the AA carriers in the Amy and NAcc. The present study demonstrates BPND changes induced by avnic smoking in OPRM1 *G carriers were blunted compared to the AA carriers. Also *G smokers had less free mu opioid receptor availability in Amy and NAcc. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Jan 2015 · Progress in Neuro-Psychopharmacology and Biological Psychiatry
    • "The pgACC, cytoarchitecturally and physiologically distinct subregion of the ACC, is involved in the processing of negative and positive emotions and affective component of pain and has anatomical connections to other core-emotional processing regions as amygdala, PAG, and hypothalamus (An et al. 1998; Beckmann et al. 2009). Imaging studies using the selective μ-opioid receptor agonist [ 11 C]carfentanyl, or nonselective opioid antagonist naloxone, identified a critical role of the EOS in control of these processes in the pgACC (Kennedy et al. 2006; Wager et al. 2007; Eippert et al. 2009). Analysis of the mechanisms underlying the neurochemical basis of lateralized function in the pgACC is clinically important, because abnormalities in this area are associated with depression, schizophrenia , borderline personality, and anxiety disorders (Fahim et al. 2005; Walter et al. 2009; Prossin et al. 2010; Pizzagalli 2011), and autism spectrum disorder including Asperger syndrome (Oner et al. 2007). "
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    ABSTRACT: Lateralization of the processing of positive and negative emotions and pain suggests an asymmetric distribution of the neurotransmitter systems regulating these functions between the left and right brain hemispheres. By virtue of their ability to selectively mediate euphoria, dysphoria, and pain, the μ-, δ-, and κ-opioid receptors and their endogenous ligands may subserve these lateralized functions. We addressed this hypothesis by comparing the levels of the opioid receptors and peptides in the left and right anterior cingulate cortex (ACC), a key area for emotion and pain processing. Opioid mRNAs and peptides and 5 "classical" neurotransmitters were analyzed in postmortem tissues from 20 human subjects. Leu-enkephalin-Arg (LER) and Met-enkephalin-Arg-Phe, preferential δ-/μ- and κ-/μ-opioid agonists, demonstrated marked lateralization to the left and right ACC, respectively. Dynorphin B (Dyn B) strongly correlated with LER in the left, but not in the right ACC suggesting different mechanisms of the conversion of this κ-opioid agonist to δ-/μ-opioid ligand in the 2 hemispheres; in the right ACC, Dyn B may be cleaved by PACE4, a proprotein convertase regulating left-right asymmetry formation. These findings suggest that region-specific lateralization of neuronal networks expressing opioid peptides underlies in part lateralization of higher functions, including positive and negative emotions and pain in the human brain.
    No preview · Article · Jan 2015 · Cerebral Cortex
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