Chapter 3 – Comprehensive review 93 nocebo hyperalgesia affected a specific biochemical pain pathway related to PG synthesis; however, in the absence of hypoxia-related activation of the COX-PG pathway, negative expectations were insufficient in initiating pain and PG synthesis. While these results highlighted a role of peripheral biochemicals that are directly related to pain signaling in nocebo hyperalgesia, they also pinpoint that nocebo hyperalgesia may be dependent on the intensity of an underlying pain. Functional imaging studies have also implicated sensory discrimination in nocebo hyperalgesia, evident through the involvement of brain areas such as the thalamus and somatosensory cortex 41,61. Interestingly, pain transmission via the spinal cord under nocebo hyperalgesic conditions also reveals vast similarities between the typical perception of a high pain stimulus and the perception of high pain resulting from expectations under hyperalgesic conditions 62,63. Future studies could integrate the measures used in the abovementioned studies to cross-validate their results and achieve a more specific characterization of the various components involved in nocebo hyperalgesia. For example, peripheral components such as those found in Benedetti et al. (2014) may interact with peripheral or spinal components such as those discussed by Tinnerman and colleagues (2017) and a targeted manipulation of these variables could increase the robustness and interpretability of the current literature. Pain integration and modulation While there is overlap between all pain processing components, a further possible categorization of neural mechanisms pertains to the central sensory modulation of pain. A consistent finding across the articles reviewed here is that nocebo hyperalgesia involves brain areas that are thought to be responsible for the modulation of pain signals 59,89–91. Some of these key areas include the dlPFC, OFC, and PAG 8,9,19,62.
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