220 Abstract Negative outcome expectations can increase pain sensitivity, a phenomenon known as nocebo hyperalgesia. An important process thought to be involved in nocebo hyperalgesia is associative learning. In this study, we examined how a targeted pharmacological manipulation of learning would impact nocebo responses and their brain correlates. Participants (n = 50) received either a placebo or a single 80mg dose of D-cycloserine (a partial NMDA receptor agonist) and underwent fMRI. Behavioral conditioning and negative suggestions were used to induce nocebo responses. Participants underwent pre-conditioning outside the scanner. During scanning, we first delivered baseline pain stimulations, followed by nocebo acquisition and extinction phases. During acquisition, thermal pain stimulations of high intensity were paired with the supposed activation of sham electrical stimuli (nocebo trials), whereas moderate intensity pain was administered with inactive electrical stimulation (control trials). During extinction, moderate pain was administered across both nocebo and control trials. Nocebo hyperalgesia (reported pain difference between nocebo/control trials) was induced in both groups (p < 0.001). Nocebo magnitudes and brain activations did not show significant differences between D-cycloserine and placebo. In acquisition and extinction, there were significantly increased activations bilaterally in the amygdala, ACC, and insula, during nocebo compared to control trials. Nocebo acquisition trials also showed increased vlPFC activation. Increased opercular activation differentiated nocebo-augmented pain aggravation from baseline pain. These results support the involvement of integrative cognitiveemotional processes in nocebo hyperalgesia. We discuss our findings in relation to the role of particular learning mechanisms as well as fear in central pain modulation.
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