78 solution and no nocebo manipulation. In the nocebo control group, significant nocebo hyperalgesia and HPA axis hyperactivity were observed, as shown by increased adrenocorticotropic hormone (ACTH) and cortisol plasma concentrations. Proglumide administration only blocked nocebo hyperalgesia reports but not the nocebo-induced hyperactivity of the HPA axis, while diazepam blocked both nocebo hyperalgesia and nocebo-induced HPA axis hyperactivity. Based on these results, the authors suggested that the CCK antagonist proglumide may act on anxiety-induced hyperalgesia, as proglumide affected pain but not the HPA axis. In relation to their findings that highlight two different anxiety pathways for HPA hyperactivity and hyperalgesia, they discuss that hyperalgesia may occur when anticipatory anxiety is about the pain itself 46. In a later study, Benedetti and his colleagues (2014) studied nocebo effects on hypoxia-induced headache, a symptom experienced at high altitudes due to the altered synthesis of eicosanoid signaling molecules, such as prostaglandin (PG) and thromboxane A2 (TXA2), through the cyclooxygenase (COX) enzyme at height 47. Blockade of PG synthesis with aspirin can prevent high altitude headache 48. In a social nocebo manipulation, prior to a mountaineering trip, researchers provided negative suggestions to only one participant, who communicated the suggestions to 35 of his peers. Of the participants not reached by the nocebo suggestions, 38 were allocated to a control group. Participants visited a research location at an altitude of 3500 meters, where headache sufferers were further subdivided into groups that received aspirin (25mg/kg), placebo, or no treatment. Salivary PG, TXA2, and cortisol were measured at sea level and at 3500 meters. Additionally, identical nocebo and control groups extracted from a separate participant sample went up to only 1500 meters, where no hypoxia is supposed to take place, and underwent the same procedures. At 3500 meters, headache occurrence and intensity were significantly higher in the nocebo group relative to the control group. Larger increases in PG and TXA2 were
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