Chapter 3 – Comprehensive review 97 and long-term potentiation being central mediating factors of nocebo effects 112–114. Anxiety and fear In the induction of nocebo hyperalgesia, anxiety and stress have long been thought to be modulatory factors. Benedetti and colleagues (2006), distinguished between different physiological anxiety pathways and pointed towards a potential distinction of HPA-mediated anxiety and anxiety related specifically to pain, with the latter being a potential contributor to nocebo hyperalgesia. However, the studies that investigated cortisol, a key chemical marker of stress states, found that, while cortisol seems to increase in response to pain or negative nocebo suggestions, there is no clear evidence in support of a modulatory role of the hormone on nocebo hyperalgesia (Benedetti 2006; 2014). The role of affective processing in nocebo hyperalgesia is marked by findings implicating the amygdala 20,59,63, a primary region for fear processing and evaluation. While the amygdala has been implicated in nocebo effects by only a minority of studies, it is important to note that more threatening experimental contexts or verbal suggestions may potentially enhance the involvement of this brain region in nocebo effects. As such, it seems that fear, processed by amongst others the amygdala, may be a secondary modulatory factor in nocebo hyperalgesia. Moreover, the amygdala is extensively interconnected with areas that were consistently fount to be involved in nocebo hyperalgesia, such as the PFC, especially the OFC as well as the dlPFC 115. These areas may thus play an additive role in the processing of pain under nocebo hyperalgesic conditions, especially due to their involvement in cognitiveaffective processes 116. The activation of the amygdala may not be essential, as frontal areas have also been shown to underlie nocebo hyperalgesia in the absence of an amygdala involvement 9,63.
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