Abstract
Although placebos have long been considered a nuisance in clinical research, today they represent an active and productive field of research and, because of the involvement of many mechanisms, the study of the placebo effect can actually be viewed as a melting pot of concepts and ideas for neuroscience. Indeed, there exists not a single but many placebo effects, with different mechanisms and in different systems, medical conditions, and therapeutic interventions. For example, brain mechanisms of expectation, anxiety, and reward are all involved, as well as a variety of learning phenomena, such as Pavlovian conditioning, cognitive, and social learning. There is also some experimental evidence of different genetic variants in placebo responsiveness. The most productive models to better understand the neurobiology of the placebo effect are pain and Parkinson's disease. In these medical conditions, the neural networks that are involved have been identified: that is, the opioidergic–cholecystokinergic–dopaminergic modulatory network in pain and part of the basal ganglia circuitry in Parkinson's disease. Important clinical implications emerge from these recent advances in placebo research. First, as the placebo effect is basically a psychosocial context effect, these data indicate that different social stimuli, such as words and rituals of the therapeutic act, may change the chemistry and circuitry of the patient's brain. Second, the mechanisms that are activated by placebos are the same as those activated by drugs, which suggests a cognitive/affective interference with drug action. Third, if prefrontal functioning is impaired, placebo responses are reduced or totally lacking, as occurs in dementia of the Alzheimer's type.
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References
Ader R, Cohen N (1975). Behaviourally conditioned immunosuppression. Psychosom Med 37: 333–340.
Alvarez-Buyalla R, Carrasco-Zanini J (1960). A conditioned reflex which reproduces the hypoglycemic effect of insulin. Acta Physiol Lat Am 10: 153–158.
Alvarez-Buyalla R, Segura ET, Alvarez-Buyalla ER (1961). Participation of the hypophysis in the conditioned reflex which reproduces the hypoglycemic effect of insulin. Acta Physiol Lat Am 11: 113–119.
Amanzio M, Benedetti F (1999). Neuropharmacological dissection of placebo analgesia: expectation–activated opioid systems versus conditioning–activated specific subsystems. J Neurosci 19: 484–494.
Amanzio M, Pollo A, Maggi G, Benedetti F (2001). Response variability to analgesics: a role for non-specific activation of endogenous opioids. Pain 90: 205–215.
Andre J, Zeau B, Pohl M, Cesselin F, Benoliel JJ, Becker C (2005). Involvement of cholecystokininergic system in anxiety–induced hyperalgesia in male rats: behavioral and biochemilac studies. J Neurosci 25: 7896–7904.
Bandura A (1997). Self–Efficacy: The Exercise of Control. Cambridge University Press: New York.
Basbaum AI, Fields HL (1984). Endogenous pain control systems: brainstem spinal pathways and endorphin circuitry. Ann Rev Neurosci 7: 309–338.
Batterman RC (1966). Persistence of responsiveness with placebo therapy following an effective drug trial. J New Drugs 6: 137–141.
Batterman RC, Lower WR (1968). Placebo responsiveness–influence of previous therapy. Curr Therap Res 10: 136–143.
Benedetti F (1996). The opposite effects of the opiate antagonist naloxone and the cholecystokinin antagonist proglumide on placebo analgesia. Pain 64: 535–543.
Benedetti F (2008a). Mechanisms of placebo and placebo–related effects across diseases and treatments. Annu Rev Pharmacol Toxicol 48: 33–60.
Benedetti F (2008b). Placebo Effects: Understanding the Mechanisms in Health and Disease. Oxford University Press: Oxford. This book describes the neurobiological mechanisms of different placebo effects and placebo-related effects across a variety of medical conditions, therapeutic interventions, systems and apparatuses.
Benedetti F (2010). No prefrontal control, no placebo response. Pain 148: 357–358.
Benedetti F, Amanzio M (1997). The neurobiology of placebo analgesia: from endogenous opioids to cholecystokinin. Prog Neurobiol 52: 109–125.
Benedetti F, Amanzio M, Casadio C, Oliaro A, Maggi G (1997). Blockade of nocebo hyperalgesia by the cholecystokinin antagonist proglumide. Pain 71: 135–140.
Benedetti F, Amanzio M, Maggi G (1995). Potentiation of placebo analgesia by proglumide. Lancet 346: 1231.
Benedetti F, Amanzio M, Vighetti S, Asteggiano G (2006a). The biochemical and neuroendocrine bases of the hyperalgesic nocebo effect. J Neurosci 26: 12014–12022.
Benedetti F, Arduino C, Costa S, Vighetti S, Tarenzi L, Rainero I et al (2006b). Loss of expectation-related mechanisms in Alzheimer's disease makes analgesic therapies less effective. Pain 121: 133–144. The first evidence that placebo responses are disrupted when there is an impairment of the prefrontal regions of the brain.
Benedetti F, Colloca L, Torre E, Lanotte M, Melcarne A, Pesare M et al (2004). Placebo–responsive Parkinson patients show decreased activity in single neurons of subthalamic nucleus. Nat Neurosci 7: 587–588. This paper provides the first evidence of a placebo effect at the single-neuron level, showing that a placebo procedure affects specific neuronal populations.
Benedetti F, Lanotte M, Colloca L, Ducati A, Zibetti M, Lopiano L (2009). Electrophysiological properties of thalamic, subthalamic and nigral neurons during the anti-parkinsonian placebo response. J Physiol 587: 3869–3883.
Benedetti F, Maggi G, Lopiano L, Colloca L (2007). When words are painful–unraveling the mechanisms of the nocebo effect. Neuroscience 147: 260–271.
Benedetti F, Maggi G, Lopiano L, Lanotte M, Rainero I, Vighetti S et al (2003a). Open versus hidden medical treatments: the patient's knowledge about a therapy affects the therapy outcome. Prev Treat 6. Available at http://psycnet.apa.org/index.cfm?fa=search.displayRecord&uid=2003-07872-001.
Benedetti F, Mayberg HS, Wager TD, Stohler CS, Zubieta JK (2005). Neurobiological mechanisms of the placebo effect. J Neurosci 25: 10390–10402.
Benedetti F, Pollo A, Lopiano L, Lanotte M, Vighetti S, Rainero I (2003b). Conscious expectation and unconscious conditioning in analgesic, motor and hormonal placebo–nocebo responses. J Neurosci 23: 4315–4323.
Berman KF, Ostrem JL, Randolph C, Gold J, Goldberg TE, Coppola R et al (1995). Physiological activation of a cortical network during performance of the Wisconsin Card Sorting Test: a positron emission tomography study. Neuropsychologia 33: 1027–1046.
Bootzin RR (1985). The role of expectancy in behavior change. In: White L, Tursky B, Schwartz GE (eds). Placebo: Theory, Research, and Mechanisms. Guilford Press: New York. pp 196–210.
Bootzin RR, Caspi O (2002). Explanatory mechanisms for placebo effects: cognition, personality and social learning. In: HA Guess, A Kleinman, JW Kusek, LW Engel (eds). The Science of the Placebo: Toward an Interdisciplinary Research Agenda. BMJ Books: London, UK. pp 108–132.
Chua P, Krams M, Toni I, Passingham R, Dolan R (1999). A functional anatomy of anticipatory anxiety. Neuroimage 9: 563–571.
Colloca L, Benedetti F (2005). Placebos and painkillers: is mind as real as matter? Nat Rev Neurosci 6: 545–552.
Colloca L, Benedetti F (2006). How prior experience shapes placebo analgesia. Pain 124: 126–133.
Colloca L, Benedetti F (2007). Nocebo hyperalgesia: how anxiety is turned into pain. Curr Opin Anaesthesiol 20: 435–439.
Colloca L, Benedetti F (2009). Placebo analgesia induced by social observational learning. Pain 144: 28–34.
Colloca L, Lopiano L, Lanotte M, Benedetti F (2004). Overt versus covert treatment for pain, anxiety and Parkinson's disease. Lancet Neurol 3: 679–684.
Colloca L, Sigaudo M, Benedetti F (2008). The role of learning in nocebo and placebo effects. Pain 136: 211–218.
de la Fuente–Fernandez R, Phillips AF, Zamburlini M, Sossi V, Calne DB, Ruth TJ et al (2002). Dopamine release in human ventral striatum and expectation of reward. Behav Brain Res 96: 393–402.
de la Fuente–Fernandez R, Ruth TJ, Sossi V, Schulzer M, Calne DB, Stoessl AJ (2001). Expectation and dopamine release: mechanisms of the placebo effect in Parkinson's disease. Science 293: 1164–1166. This is the first imaging study of the placebo effect, showing a dopamine release in Parkinson's disease.
Eippert F, Bingel U, Schoell ED, Yacubian J, Klinger R, Lorenz J et al (2009a). Activation of the opioidergic descending pain control system underlies placebo analgesia. Neuron 63: 533–543.
Eippert F, Finsterbusch J, Bingel U, Büchel C (2009b). Direct evidence for spinal cord involvement in placebo analgesia. Science 326: 404. In this paper, the placebo analgesic response is also found to involve the spinal cord, thus showing that placebos may affect early processing of nociceptive information.
Enck P, Benedetti F, Schedlowski M (2008). New insights into the placebo and nocebo responses. Neuron 59: 195–206. This comprehensive review summarizes the current neurobiological models of both placebo and nocebo phenomena.
Evans FJ (1977). The placebo control of pain: a paradigm for investigating non–specific effects in psychotherapy. In: JP Brady, J Mendels, WR Reiger, MT Orne (eds). Psychiatry: Areas of Promise and Advancement. Plenum Press: New York. pp 249–271.
Finniss DG, Kaptchuk TJ, Miller F, Benedetti F (2010). Biological, clinical, and ethical advances of placebo effects. Lancet 375: 686–695.
Flor H, Grüsser SM (1999). Conditioned stress-induced analgesia in humans. Eur J Pain 3: 317–324.
Frank JD (1971). Therapeutic factors in psychotherapy. Am J Psychother 25: 350–361.
Furmark T, Appel L, Henningsson S, Ahs F, Faria V, Linnman C et al (2008). A link between serotonin-related gene polymorphisms, amygdala activity, and placebo-induced relief from social anxiety. J Neurosci 28: 13066–13074. This study shows, for the first time, evidence of a link between genetically controlled serotonergic modulation of amygdala activity and placebo-induced anxiety relief.
Goebel MU, Hubell D, Kou W, Janssen OE, Katsarava Z, Limmroth V et al (2005). Behavioural conditioning with interferon beta-1a in humans. Physiol Behav 84: 807–814.
Goebel MU, Meykadeh N, Kou W, Schedlowski M, Hengge UR (2009). Behavioural conditioning of antihistamine effects in patients with allergic rhinitis. Psychother Psychosom 77: 227–234.
Goebel MU, Trebst AE, Steiner J, Xie YF, Exton MS, Frede S et al (2002). Behavioural conditioning of immunosuppression is possible in humans. FASEB J 16: 1869–1873. This paper clearly shows that behavioral conditioning is possible in the human immune system, and indicates that placebo immune responses are mediated by classical conditioning in humans.
Hebb ALO, Poulin J–F, Roach SP, Zacharko RM, Drolet G (2005). Cholecystokinin and endogenous opioid peptides: interactive influence on pain, cognition, and emotion. Prog Neuropsychopharmacol Biol Psychiatry 29: 1225–1238.
Heinricher MM, McGaraughty S, Tortorici V (2001). Circuitry underlying antiopioid actions of cholecystokinin within the rostral ventromedial medulla. J Neurophysiol 85: 280–286.
Heinricher MM, Neubert MJ (2004). Neural basis for the hyperalgesic action of cholecystokinin in the rostral ventromedial medulla. J Neurophysiol 92: 1982–1989.
Herrnstein RJ (1962). Placebo effect in the rat. Science 138: 677–678.
Hsieh JC, Stone–Elander S, Ingvar M (1999). Anticipatory coping of pain expressed in the human anterior cingulate cortex: a positron emission tomography study. Neurosci Lett 262: 61–64.
Kalivas PW, Churchill L, Romanides A (1999). Involvement of the pallidal–thalamocortical circuit in adaptive behavior. Ann NY Acad Sci 877: 64–70.
Kaptchuk T, Kelley JM, Deykin A, Wayne PM, Lasagna LC, Epstein IO et al (2008). Do ‘placebo responders’ exist? Contemp Clin Trials 29: 587–595.
Keltner JR, Furst A, Fan C, Redfern R, Inglis B, Fields HL (2006). Isolating the modulatory effect of expectation on pain transmission: a functional magnetic imaging study. J Neurosci 26: 4437–4443.
Kirsch I (1999). How Expectancies Shape Experience. American Psychological Association: Washington DC.
Kirsch I, Sapirstein G (1998). Listening to Prozac but hearing placebo: a meta–analysis of antidepressant medication. Prev Treat 1 Article 0002a (originally published online 1 February 2003, at http://journals.apa.org/prevention/volume1/pre0010002a.html).
Kirsch I, Lynn SJ, Vigorito M, Miller RR (2004). The role of cognition in classical and operant conditioning. J Clin Psychol 60: 369–392.
Kong J, Gollub RL, Polich G, Kirsch I, LaViolette P, Vangel M et al (2008). A functional magnetic resonance imaging study on the neural mechanisms of hyperalgesic nocebo effect. J Neurosci 28: 13354–13362.
Konishi S, Kawazu M, Uchida I, Kikyo H, Asakura I, Miyashita Y (1999a). Contribution of working memory to transient activation in human inferior prefrontal cortex during performance of the Wisconsin Card Sorting Test. Cereb Cortex 9: 745–753.
Konishi S, Nakajima K, Uchida I, Kameyama M, Nakahara K, Sekihara K et al (1998). Transient activation of inferior prefrontal cortex during cognitive set shifting. Nat Neurosci 1: 80–84.
Konishi S, Nakajima K, Uchida I, Kikyo H, Kameyama M, Miyashita Y (1999b). Common inhibitory mechanism in human inferior prefrontal cortex revealed by event-related functional MRI. Brain 122: 981–991.
Koyama T, McHaffie JG, Laurienti PJ, Coghill RC (2005). The subjective experience of pain: where expectations became reality. Proc Nat Acad Sci USA 102: 12950–12955.
Koyama T, Tanaka YZ, Mikami A (1998). Nociceptive neurons in the macaque anterior cingulated activate during anticipation of pain. NeuroReport 9: 2663–2667.
Krummenacher P, Candia V, Folkers G, Schedlowski M, Schönbächler G (2010). Prefrontal cortex modulates placebo analgesia. Pain 148: 368–374. This study shows that the inactivation of the dorsolateral prefrontal cortex prevents placebo analgesia.
Laska E, Sunshine A (1973). Anticipation of analgesia: a placebo effect. Headache 13: 1–11.
Last JM (1983). A Dictionary of Epidemiology. Oxford University Press: New York.
Leuchter AF, McCracken JT, Hunter AM, Cook IA, Alpert JE (2009). Monoamine oxidase a and catechol-o-methyltransferase functional polymorphisms and the placebo response in major depressive disorder. J Clin Psychopharmacol 29: 372–377.
Levine JD, Gordon NC (1984). Influence of the method of drug administration on analgesic response. Nature 312: 77–94.
Levine JD, Gordon NC, Fields HL (1978). The mechanisms of placebo analgesia. Lancet 2: 654–657.
Levine JD, Gordon NC, Smith R, Fields HL (1981). Analgesic responses to morphine and placebo in individuals with postoperative pain. Pain 10: 379–389.
Lichko AE (1959). Conditioned reflex hypoglycemia in man. Pavlov J High Nerv Activity 9: 731–737.
Lorenz J, Hauck M, Paur RC, Nakamura Y, Zimmerman R, Bromm B et al (2005). Cortical correlates of false expectations during pain intensity judgments–a possible manifestation of placebo/nocebo cognitions. Brain Behav Immun 19: 283–295.
Mayberg HS, Silva JA, Brannan SK, Tekell JL, Mahurin RK, McGinnis S et al (2002). The functional neuroanatomy of the placebo. Am J Psychiatry 159: 728–737.
McGlashan TH, Evans FJ, Orne MT (1969). The nature of hypnotic analgesia and placebo response to experimental pain. Psychosom Med 31: 227–246.
Mitchell JM, Lowe D, Fields HL (1998). The contribution of the rostral ventromedial medulla to the antinociceptive effects of systemic morphine in restrained and unrestrained rats. Neuroscience 87: 123–133.
Moerman DE (2002). Meaning, Medicine and the Placebo Effect. Cambridge University Press: Cambridge.
Mogenson GJ, Yang CA (1991). The contribution of basal forebrain to limbic–motor integration and the mediation of motivation to action. Adv Exp Med Biol 295: 267–290.
Montgomery GH, Kirsch I (1997). Classical conditioning and the placebo effect. Pain 72: 107–113.
Nagahama Y, Fukuyama H, Yamauchi H (1996). Cerebral activation during performance of a card-sorting test. Brain 119: 1667–1675.
Noble F, Wank SA, Crawley JN, Bradwejn J, Seroogy KB, Hamon M et al (1999). International Union of Pharmacology. XXI. Structure, distribution, and functions of cholecystokinin receptors. Pharmacol Rev 51: 745–781.
Pacheco-Lopez G, Engler H, Niemi MB, Schedlowski M (2006). Expectations and associations that heal: immunomodulatory placebo effects and its neurobiology. Brain Behav Immun 20: 430–446. This article reviews the state of the art of immune placebo responses in both humans and animals.
Pacheco-Lopez G, Niemi MB, Kou W, Harting M, Fandrey J, Schedlowski M (2005). Neural substrates for behaviourally conditioned immunosuppression in the rat. J Neurosci 25: 2330–2337.
Petrovic P, Dietrich T, Fransson P, Andersson J, Carlsson K (2005). Placebo in emotional processing–induced expectations of anxiety relief activate a generalized modulatory network. Neuron 46: 957–969.
Petrovic P, Kalso E, Petersson KM, Ingvar M (2002). Placebo and opioid analgesia–imaging a shared neuronal network. Science 295: 1737–1740. This positron emission tomography study shows similar brain responses to opioids and to placebos, which suggest that they share a common neural network.
Ploghaus A, Narain C, Beckmann CF, Clare S, Bantick S, Wise R et al (2001). Exacerbation of pain by anxiety is associated with activity in a hippocampal network. J Neurosci 21: 9896–9903.
Ploghaus A, Tracey I, Gati JS, Clare S, Menon RS, Matthews PM et al (1999). Dissociating pain from its anticipation in the human brain. Science 64: 1979–1981.
Pollo A, Carlino E, Benedetti F (2008). The top–down influence of ergogenic placebos on muscle work and fatigue. Eur J Neurosci 28: 379–388.
Pollo A, Torre E, Lopiano L, Rizzone M, Lanotte M, Cavanna A et al (2002). Expectation modulates the response to subthalamic nucleus stimulation in Parkinsonian patients. NeuroReport 13: 1383–1386.
Porro CA, Baraldi P, Pagnoni G, Serafini M, Facchin P, Maieron M et al (2002). Does anticipation of pain affect cortical nociceptive systems? J Neurosci 22: 3206–3214.
Porro CA, Cettolo V, Francescato MP, Baraldi P (2003). Functional activity mapping of the mesial hemispheric wall during anticipation of pain. Neuroimage 19: 1738–1747.
Price DD, Finniss DG, Benedetti F (2008). A comprehensive review of the placebo effect: recent advances and current thought. Annu Rev Psychol 59: 565–590.
Price DD, Milling LS, Kirsch I, Duff A, Montgomery GH, Nicholls SS (1999). An analysis of factors that contribute to the magnitude of placebo analgesia in an experimental paradigm. Pain 83: 147–156.
Rausch JL, Johnson ME, Fei YJ, Li JQ, Shendarkar N, Hobby HM et al (2002). Initial conditions of serotonin transporter kinetics and genotype: influence on SSRI treatment trial outcome. Biol Psychiatry 51: 723–732.
Reiss S (1980). Pavlovian conditioning and human fear: an expectancy model. Behav Ther 11: 380–396.
Rescorla RA (1988). Pavlovian conditioning: it's not what you think it is. Am Psychol 43: 151–160.
Rolls ET, Critchley HD, Mason R, Wakeman EA (1996). Orbitofrontal cortex neurons: role in olfactory and visual association learning. J Neurophysiol 75: 1970–1981.
Sawamoto N, Honda M, Okada T, Hanakawa T, Kanda M, Fukuyama H et al (2000). Expectation of pain enhances responses to non-painful somatosensory stimulation in the anterior cingulate cortex and parietal operculum/posterior insula: an event-related functional magnetic resonance imaging study. J Neurosci 20: 7438–7445.
Schultz W (2006). Behavioral theories and the neurophysiology of reward. Ann Rev Psychol 57: 87–115.
Schweinhardt P, Seminowicz DA, Jaeger E, Duncan GH, Bushnell MC (2009). The anatomy of the mesolimbic reward system: a link between personality and the placebo analgesic response. J Neurosci 29: 4882–4887.
Scott DJ, Stohler CS, Egnatuk CM, Wang H, Koeppe RA, Zubieta JK (2007). Individual differences in reward responding explain placebo–induced expectations and effects. Neuron 55: 325–336. This paper suggests that placebo responsiveness depends on the efficiency of reward mechanisms, for a correlation between placebo responses and monetary rewards was observed.
Scott DJ, Stohler CS, Egnatuk CM, Wang H, Koeppe RA, Zubieta JK (2008). Placebo and nocebo effects are defined by opposite opioid and dopaminergic responses. Arch Gen Psychiatry 65: 1225–1226.
Setlow B, Schoenbaum G, Gallagher M (2003). Neural encoding in ventral striatum during olfactory discrimination learning. Neuron 38: 625–636.
Stewart–Williams S, Podd J (2004). The placebo effect: dissolving the expectancy versus conditioning debate. Psychol Bull 130: 324–340.
Stockhorst U, Gritzmann E, Klopp K, Schottenfeld-Naor Y, Hübinger A, Berresheim HW et al (1999). Classical conditioning of insulin effects in healthy humans. Psychosom Med 61: 424–435.
Stockhorst U, Steingruber HJ, Scherbaum WA (2000). Classically conditioned responses following repeated insulin and glucose administration in humans. Behav Brain Res 110: 143–159.
Strafella AP, Ko JH, Monchi O (2006). Therapeutic application of transcranial magnetic stimulation in Parkinson's disease: the contribution of expectation. Neuroimage 31: 1666–1672.
Sunshine A, Laska E, Meisner M, Morgan S (1964). Analgesic studies of indomethacin as analyzed by computer techniques. Clin Pharmacol Ther 5: 699–707.
Terman GW, Morgan MJ, Liebeskind JC (1986). Opioid and non-opioid stress analgesia from cold-water swim: importance of stress severity. Brain Res 372: 167–171.
Thompson PM, Hayashi KM, de Zubicaray G, Janke AL, Rose SE, Semple J et al (2003). Dynamics of gray matter loss in Alzheimer's disease. J Neurosci 23: 994–1005.
Tobler PN, Fiorillo CD, Schultz W (2005). Adaptive coding of reward value by dopamine neurons. Science 307: 1642–1645.
Tolman EC (1932). Purposive Behavior in Animals and Men. Appleton Century Crofts: New York.
Vase L, Robinson ME, Verne GN, Price DD (2005). Increased placebo analgesia over time in irritable bowel syndrome (IBS) patients is associated with desire and expectation but not endogenous opioid mechanisms. Pain 115: 338–347.
Voudouris NJ, Pech CL, Coleman G (1989). Conditioned response models of placebo phenomena: further support. Pain 38: 109–116.
Voudouris NJ, Pech CL, Coleman G (1990). The role of conditioning and verbal expectancy in the placebo response. Pain 43: 121–128.
Wager TD, Billing JK, Smith EE, Sokolik A, Casey KL, Davidson RJ et al (2004). Placebo–induced changes in fMRI in the anticipation and experience of pain. Science 303: 1162–1166.
Wager TD, Scott DJ, Zubieta JK (2007). Placebo effects on human μ–opioid activity during pain. Proc Nat Acad Sci USA 104: 11056–11061.
Willer JC, Albe-Fessard D (1980). Electrophysiological evidence for a release of endogenous opiates in stress-induced ‘analgesia’ in man. Brain Res 198: 419–426.
Woods SC (1972). Conditioned hypoglycemia: effect of vagotomy and pharmacological blockade. Am J Physiol 223: 1424–1427.
Woods SC, Alexander KR, Porte Jr D (1972). Conditioned insulin secretion and hypoglycemia following repeated injections of tolbutamide in rats. Endocrinology 90: 227–231.
Woods SC, Makous W, Hutton RA (1968). A new technique for conditioned hypoglycemia. Psychon Sci 10: 389–390.
Woods SC, Makous W, Hutton RA (1969). Temporal parameters of conditioned hypoglycemia. J Comp Physiol Psychol 69: 301–307.
Zhang W, Gardell S, Zhang D, Xie JY, Agnes RS, Badghisi H et al (2009). Neuropathic pain is maintained by brainstem neurons co-expressing opioid and cholecystokinin receptors. Brain 132: 778–787.
Zubieta JK, Bueller JA, Jackson LR, Scott DJ, Xu Y, Koeppe RA et al (2005). Placebo effects mediated by endogenous opioid activity on μ-opioid receptors. J Neurosci 25: 7754–7762.
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This work was supported by grants from Regione Piemonte and Compagnia di San Paolo (Turin, Italy) and from the Volkswagen Foundation (Hannover, Germany).
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Benedetti, F., Carlino, E. & Pollo, A. How Placebos Change the Patient's Brain. Neuropsychopharmacol 36, 339–354 (2011). https://doi.org/10.1038/npp.2010.81
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