Abstract
Placebo has been reported to exert beneficial effects in patients regarding the treatment of pain. Human functional neuroimaging technology can study the intact human brain to elucidate its functional neuroanatomy and the neurobiological mechanism of the placebo effect. Blood flow measurement using functional magnetic resonance imaging and positron emission tomography (PET) has revealed that analgesia is related to decreased neural activities in pain-modulatory brain regions, such as the rostral anterior cingulate cortex (rACC), insula, thalamus, and brainstem including periaqueductal gray (PAG) and ventromedial medulla. The endogenous opioid system and its activation of μ-opioid receptors are thought to mediate the observed effects of placebo. The μ-opioid receptor-selective radiotracer-labeled PET studies show that the placebo effects are accompanied by reduction in activation of opioid neural transmission in pain-sensitive brain regions, including rACC, prefrontal cortex, insula, thalamus, amygdala, nucleus accumbens (NAC) and PAG. Further PET studies with dopamine D2/D3 receptor-labeling radiotracer demonstrate that basal ganglia including NAC are related to placebo analgesic responses. NAC dopamine release induced by placebo analgesia is related to expectation of analgesia. These data indicate that the aforementioned brain regions and neurotransmitters such as endogenous opioid and dopamine systems contribute to placebo analgesia.
Keywords: placebo, pain, functional magnetic resonance imaging, positron emission tomography, opioid, dopamine
摘要
许多文献资料报道了安慰剂对疼痛的镇痛效果。 人体大脑功能影像技术可以在无创伤条件下研究安慰剂镇痛的大脑功能解剖结构及其神经生物学机制。 功能磁共振成像和正电子发射断层扫描(PET)的脑血流测定表明大脑前扣带回喙部(rACC)、 脑岛、 丘脑和脑干的中脑导水管周围灰质(PAG)及延髓头端腹侧部的神经兴奋性降低与安慰剂镇痛调节有关。 内源性吗啡肽系统及激活吗啡肽μ受体参与安慰剂的镇痛作用。 吗啡肽μ受体标记的PET影像研究提示安慰剂镇痛伴随着疼痛相关大脑部位(如rACC、 前额叶皮层、 脑岛、 丘脑、 杏仁核、 伏隔核、 PAG 等)中内源性吗啡肽活性的降低。 此外, 标记多巴胺D2/D3 受体的PET 实验证明基底核包括伏隔核的多巴胺活性与安慰剂镇痛相关。 安慰剂镇痛引起的伏隔核的多巴胺释放与安慰剂 期待相关。 以上结果提示上述大脑区域和内源性吗啡肽及多巴胺在安慰剂镇痛方面有重要作用。
关键词: 安慰剂, 疼痛, 功能磁共振成像, 正电子发射断层扫描术, 吗啡肽, 多巴胺
References
- [1].Hróbjartsson A., Gøtzsche P.C. Is the placebo powerless? An analysis of clinical trials comparing placebo with no treatment. N Engl J Med. 2001;344:1594–1602. doi: 10.1056/NEJM200105243442106. [DOI] [PubMed] [Google Scholar]
- [2].Hróbjartsson A., Gøtzsche P.C. Is the placebo powerless? Update of a systematic review with 52 new randomized trials comparing placebo with no treatment. J Intern Med. 2004;256:91–100. doi: 10.1111/j.1365-2796.2004.01355.x. [DOI] [PubMed] [Google Scholar]
- [3].Wampold B.E., Minami T., Tierney S.C., Baskin T.W., Bhati K.S. The placebo is powerful: estimating placebo effects in medicine and psychotherapy from randomized clinical trials. J Clin Psychol. 2005;61:835–854. doi: 10.1002/jclp.20129. [DOI] [PubMed] [Google Scholar]
- [4].Melzack R., Torgerson W.S. On the language of pain. Anesthesiology. 1971;34:50–59. doi: 10.1097/00000542-197101000-00017. [DOI] [PubMed] [Google Scholar]
- [5].Vase L., Riley J.L., Price D.D. A comparison of placebo effects in clinical analgesic trials versus studies of placebo analgesia. Pain. 2002;99:443–452. doi: 10.1016/S0304-3959(02)00205-1. [DOI] [PubMed] [Google Scholar]
- [6].Benedetti F., Mayberg H.S., Wager T.D., Stohler C.S., Zubieta J.K. Neurobiological mechanisms of the placebo effect. J Neurosci. 2005;25:10390–10402. doi: 10.1523/JNEUROSCI.3458-05.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [7].Price D.D., Finniss D.G., Benedetti F. A comprehensive review of the placebo effect: recent advances and current thought. Annu Rev Psychol. 2008;59:565–590. doi: 10.1146/annurev.psych.59.113006.095941. [DOI] [PubMed] [Google Scholar]
- [8].Zubieta J.K., Stohler C.S. Neurobiological mechanisms of placebo responses. Ann N Y Acad Sci. 2009;1156:198–210. doi: 10.1111/j.1749-6632.2009.04424.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [9].Wager T.D., Rilling J.K., Smith E.E., Sokolik A., Casey K.L., Davidson R.J., et al. Placebo-induced changes in FMRI in the anticipation and experience of pain. Science. 2004;303:1162–1167. doi: 10.1126/science.1093065. [DOI] [PubMed] [Google Scholar]
- [10].Logothetis N.K., Pauls J., Augath M., Trinath T., Oeltermann A. Neurophysiological investigation of the basis of the fMRI signal. Nature. 2001;412:150–157. doi: 10.1038/35084005. [DOI] [PubMed] [Google Scholar]
- [11].Bingel U., Lorenz J., Schoell E., Weiller C., Büchel C. Mechanisms of placebo analgesia: rACC recruitment of a subcortical antinociceptive network. Pain. 2006;120:8–15. doi: 10.1016/j.pain.2005.08.027. [DOI] [PubMed] [Google Scholar]
- [12].Petrovic P., Kalso E., Petersson K.M., Ingvar M. Placebo and opioid analgesia-imaging a shared neuronal network. Science. 2002;295:1737–1740. doi: 10.1126/science.1067176. [DOI] [PubMed] [Google Scholar]
- [13].Eippert F., Bingel U., Schoell E.D., Yacubian J., Klinger R., Lorenz J., et al. Activation of the opioidergic descending pain control system underlies placebo analgesia. Neuron. 2009;63:533–543. doi: 10.1016/j.neuron.2009.07.014. [DOI] [PubMed] [Google Scholar]
- [14].Miller E.K., Cohen J.D. An integrative theory of prefrontal cortex function. Annu Rev Neurosci. 2001;24:167–202. doi: 10.1146/annurev.neuro.24.1.167. [DOI] [PubMed] [Google Scholar]
- [15].Vogt B.A., Sikes R.W., Vogt L.J. Anterior cingulate cortex and the medial pain system. In: Gabriel M., editor. Neurobiology of cingulate cortex and limbic thalamus: a comprehensive handbook. Boston, MA: Birkhäuser; 1993. pp. 313–344. [Google Scholar]
- [16].Fields H.L. Pain modulation: expectation, opioid analgesia and virtual pain. Prog Brain Res. 2000;122:245–253. doi: 10.1016/S0079-6123(08)62143-3. [DOI] [PubMed] [Google Scholar]
- [17].Levine J.D., Gordon N.C., Fields H.L. The mechanism of placebo analgesia. Lancet. 1978;2:654–657. doi: 10.1016/S0140-6736(78)92762-9. [DOI] [PubMed] [Google Scholar]
- [18].Gracely R.H., Dubner R., Wolskee P.J., Deeter W.R. Placebo and naloxone can alter post-surgical pain by separate mechanisms. Nature. 1983;306:264–265. doi: 10.1038/306264a0. [DOI] [PubMed] [Google Scholar]
- [19].Grevert P., Albert L., Goldstein A. Partial antagonism of placebo analgesia by naloxone. Pain. 1983;16:129–143. doi: 10.1016/0304-3959(83)90203-8. [DOI] [PubMed] [Google Scholar]
- [20].Levine J.D., Gordon N.C. Influence of the method of drug administration on analgesic response. Nature. 1984;312:755–756. doi: 10.1038/312755a0. [DOI] [PubMed] [Google Scholar]
- [21].Benedetti F. The opposite effects of the opiate antagonist naloxone and the cholecystokinin antagonist proglumide on placebo analgesia. Pain. 1996;64:535–543. doi: 10.1016/0304-3959(95)00179-4. [DOI] [PubMed] [Google Scholar]
- [22].Zubieta J.K., Smith Y., Bueller J., Xu Y., Kilbourn M., Meyer C., et al. Regional mu opioid receptor regulation of sensory and affective dimensions of pain. Science. 2001;293:311–315. doi: 10.1126/science.1060952. [DOI] [PubMed] [Google Scholar]
- [23].Zubieta J.K., Smith Y., Bueller J., Xu Y., Woike T., Kilbourn M., et al. μ-Opioid receptor mediated antinociception differs in men and women. J Neurosci. 2002;22:5100–5107. doi: 10.1523/JNEUROSCI.22-12-05100.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [24].Zubieta J.K., Heitzeg M.M., Smith Y.R., Bueller J.A., Xu K., Xu Y., et al. COMT val158met genotype affects mu-opioid neurotransmitter responses to a pain stressor. Science. 2003;299:1240–1243. doi: 10.1126/science.1078546. [DOI] [PubMed] [Google Scholar]
- [25].Wager T.D., Scott D.J., Zubieta J.K. Placebo effects on human muopioid activity during pain. Proc Natl Acad Sci U S A. 2007;104:11056–11061. doi: 10.1073/pnas.0702413104. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [26].Zubieta J.K., Bueller J.A., Jackson L.R., Scott D.J., Xu Y., Koeppe R.A., et al. Placebo effects mediated by endogenous opioid activity on m-opioid receptors. J Neurosci. 2005;25:7754–7762. doi: 10.1523/JNEUROSCI.0439-05.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [27].Scott D.J., Stohler C.S., Egnatuk C.M., Wang H., Koeppe R.A., Zubieta J.K. Placebo and nocebo effects are defined by opposite opioid and dopaminergic responses. Arch Gen Psychiatry. 2008;65:220–231. doi: 10.1001/archgenpsychiatry.2007.34. [DOI] [PubMed] [Google Scholar]
- [28].Vase L., Robinson M.E., Verne G.N., Price D.D. Increased placebo analgesia over time in irritable bowel syndrome (IBS) patients is associated with desire and expectation but not endogenous opioid mechanisms. Pain. 2005;115:338–347. doi: 10.1016/j.pain.2005.03.014. [DOI] [PubMed] [Google Scholar]
- [29].de la Fuente-Fernández R., Ruth T.J., Sossi V., Schulzer M., Calne D.B., Stoessl A.J. Expectation and dopamine release: mechanism of the placebo effect in Parkinson’s disease. Science. 2001;293:1164–1166. doi: 10.1126/science.1060937. [DOI] [PubMed] [Google Scholar]
- [30].de la Fuente-Fernández R., Phillips A.G., Zamburlini M., Sossi V., Calne D.B., Ruth T.J., et al. Dopamine release in human ventral striatum and expectation of reward. Behav Brain Res. 2002;136:359–363. doi: 10.1016/S0166-4328(02)00130-4. [DOI] [PubMed] [Google Scholar]
- [31].Scott D.J., Stohler C.S., Egnatuk C.M., Wang H., Koeppe R.A., Zubieta J.K. Individual differences in reward responding explain placebo-induced expectations and effects. Neuron. 2007;55:325–336. doi: 10.1016/j.neuron.2007.06.028. [DOI] [PubMed] [Google Scholar]
