The nociceptive system is now recognized as a sensory system in its own right, from primary afferents to multiple brain areas. Pain experience is strongly modulated by interactions of ascending and descending pathways. Understanding these modulatory mechanisms in health and in disease is critical for developing fully effective therapies for the treatment of clinical pain conditions.

Reductions in pain ratings when administered a placebo with expected analgesic properties have been described and hypothesized to be mediated by the pain-suppressive endogenous opioid system. Using molecular imaging techniques, we directly examined the activity of the endogenous opioid system on -opioid receptors in humans in sustained pain with and without the administration of a placebo. Significant placebo-induced activation of -opioid receptor-mediated neurotransmission was observed in both higher-order and subcortical brain regions, which included the pregenual and subgenual rostral anterior cingulate, the dorsolateral prefrontal cortex, the insular cortex, and the nucleus accumbens. Regional activations were paralleled by lower ratings of pain intensity, reductions in its sensory and affective qualities, and in the negative emotional state of the volunteers. These data demonstrate that cognitive factors (e.g., expectation of pain relief) are capable of modulating physical and emotional states through the site-specific activation of -opioid receptor signaling in the human brain.

Placebo and nocebo effects are associated with opposite responses of DA and endogenous opioid neurotransmission in a distributed network of regions. The brain areas involved in these phenomena form part of the circuit typically implicated in reward responses and motivated behavior.

Understanding inter-individual differences in stress response requires the explanation of genetic influences at multiple phenotypic levels, including complex behaviours and the metabolic responses of brain regions to emotional stimuli. Neuropeptide Y (NPY) is anxiolytic 1,2 and its release is induced by stress 3 . NPY is abundantly expressed in regions of the limbic system that are implicated in arousal and in the assignment of emotional valences to stimuli and memories [4][5][6] . Here we show that haplotype-driven NPY expression predicts brain responses to emotional and stress challenges and also inversely correlates with trait anxiety. NPY haplotypes predicted levels of NPY messenger RNA in postmortem brain and lymphoblasts, and levels of plasma NPY. Lower haplotype-driven NPY expression predicted higher emotion-induced activation of the amygdala, as well as diminished resiliency as assessed by pain/stress-induced activations of endogenous opioid neurotransmission in various brain regions. A single nucleotide polymorphism (SNP rs16147) located in the promoter region alters NPY expression in vitro and seems to account for more than half of the variation in expression in vivo. These convergent findings are consistent with the function of NPY as an anxiolytic peptide and help to explain inter-individual variation in resiliency to stress, a risk factor for many diseases.Reprints and permissions information is available at www.nature.com/reprints. Correspondence and requests for materials should be addressed to D.G. (E-mail: davidgoldman@mail.nih.gov). * These authors contributed equally to this work. † Present address: Innovation Centre China, AstraZeneca Global R&D, Shanghai 201203, China. Supplementary Fig. 1b). Five haplotypes (H1-H5) account for 93.8% of chromosomes in this block (Fig. 1a).We observed haplotype-driven NPY mRNA expression in postmortem brain (US Caucasians, Miami sample) by detecting the differential expression of alleles at single nucleotide polymorphism (SNP) rs5574 C/T, selected because of its high frequency and location in the transcript. Of these 28 samples, chosen because all were heterozygous for rs5574, 16 (57%) showed differential allele expression at an allele ratio of more than 1.2, in either direction. H1 and H4 were low-expression haplotypes, H2 was high, H3 was intermediate and H5 was unclassified because only two H1/H5 heterozygous brains were available (Fig. 1b). This expression-based functional classification is consistent with a cladistically based clustering of haplotypes, indicating that expression variation is linked to gene ancestry (Fig. 1a). The effects on expression of the more common H1, H2 and H3 haplotypes were verified in 47 lymphoblastoid cell lines derived from healthy Finnish men ( Fig. 1c) representing the six common diplotypes (72% of all diplotypes). On the basis of lymphoblast NPY mRNA levels, the expression value for each haplotype was calculated by regression analysis. Expression values for the six common diplotypes were well predicted under a co...

Expectations, positive or negative, are modulating factors influencing behavior. They are also thought to underlie placebo effects, impacting perceptions and biological processes. Using healthy human subjects, we examined the role of the nucleus accumbens (NAC), a region centrally involved in the encoding of reward expectation, in the formation of placebo responses. Employing functional molecular imaging, activation of NAC dopamine (DA) release was observed during placebo administration and related to its anticipated effects, perception-anticipation mismatches, and placebo effect development. In additional functional MRI studies, the expectation of monetary gain increased NAC synaptic activity in a manner proportional to placebo-induced DA release, anticipated effects, perception-anticipation differentials, and actual placebo effects. Individual variations in NAC response to reward expectation accounted for 28% of the variance in the formation of placebo analgesia.