Peciña Marta, Love Tiffany, Stohler Christian S, Goldman David, Zubieta Jon-Kar
Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA.
College of Dental Medicine, Columbia University, New York, NY, USA.
Neuropsychopharmacology. 2015 Mar;40(4):957-65. doi: 10.1038/npp.2014.272. Epub 2014 Oct 13.
Mu-opioid receptors (MOPRs) are critically involved in the modulation of pain and analgesia, and represent a candidate mechanism for the development of biomarkers of pain conditions and their responses to treatment. To further understand the human implications of genetic variation within the opioid system in pain and opioid-mediated placebo responses, we investigated the association between the functional single-nucleotide polymorphism (SNP) in the μ-opioid receptor gene (OPRM1), A118G, and psychophysical responses, personality traits, and neurotransmitter systems (dopamine (DA), opioid) related to pain and placebo analgesia. OPRM1 G carriers, compared with AA homozygotes, showed an overall reduction of baseline μ-opioid receptor availability in regions implicated in pain and affective regulation. In response to a sustained painful stimulus, we found no effect of A118G on pain-induced endogenous opioid release. Instead, AA homozygotes showed a blunted DA response in the nucleus accumbens (NAc) in response to the pain challenge. After placebo administration, G carriers showed more pronounced mood disturbances and lower placebo-induced μ-opioid system activation in the anterior insula (aINS), the amygdala (AMY), the NAc, the thalamus (THA), and the brainstem, as well as lower levels of DA D2/3 activation in the NAc. At a trait level, G carriers reported higher NEO-Neuroticism scores; a personality trait previously associated with increased pain and lower placebo responses, which were negatively correlated with baseline μ-opioid receptor availability in the aINS and subgenual anterior cingulate cortex (sgACC). Our results demonstrate that the A118G OPRM1 polymorphism contributes to interindividual variations in the function of neurotransmitters responsive to pain (endogenous opioid and dopamine), as well as their regulation through cognitive-emotional influences in the context of therapeutic expectations, the so-called placebo effect. These effects are relevant to human vulnerability to disease processes where these neurotransmitters have a role, such as persistent pain, mood, and substance use disorders, and responses to their treatments.
μ-阿片受体（MOPRs）在疼痛调节和镇痛中起关键作用，是疼痛状况生物标志物及其对治疗反应的潜在机制。为了进一步了解阿片系统内基因变异对人类疼痛及阿片介导的安慰剂反应的影响，我们研究了μ-阿片受体基因（OPRM1）功能性单核苷酸多态性（SNP）A118G与心理物理反应、人格特质以及与疼痛和安慰剂镇痛相关的神经递质系统（多巴胺（DA）、阿片类物质）之间的关联。与AA纯合子相比，OPRM1 G携带者在与疼痛和情感调节相关的区域中，基线μ-阿片受体可用性总体降低。在持续疼痛刺激下，我们发现A1A8G对疼痛诱导的内源性阿片类物质释放没有影响。相反，AA纯合子在伏隔核（NAc）中对疼痛刺激的DA反应减弱。给予安慰剂后，G携带者表现出更明显的情绪障碍，并且在前脑岛（aINS）、杏仁核（AMY）、NAc、丘脑（THA）和脑干中，安慰剂诱导的μ-阿片系统激活较低，同时NAc中DA D2/3激活水平也较低。在特质水平上，G携带者报告的NEO-神经质得分较高；这是一种先前与疼痛增加和安慰剂反应降低相关的人格特质，与aINS和膝下前扣带回皮质（sgACC）中的基线μ-阿片受体可用性呈负相关。我们的结果表明，OPRM1 A118G多态性导致了对疼痛有反应的神经递质（内源性阿片类物质和多巴胺）功能的个体差异，以及在治疗期望背景下通过认知-情感影响对它们的调节，即所谓的安慰剂效应。这些效应与人类对这些神经递质起作用的疾病过程（如持续性疼痛、情绪和物质使用障碍）的易感性及其治疗反应相关。
