272 level associative learning mechanism may be at the core of acquiring learned effects on pain. On the other hand, it appears that fear-related learning, that may take place in subcortical loops, mediates pain worsening, and may be associated to pain chronification. In our research, overall, learning through the integration of experiences and pain processing may be differentiated from fear-learning under nocebo hyperalgesic conditions. In chapters 3, 4, and 5 we discussed a mediating role of uncertainty and fear in nocebo hyperalgesia. However, in chapter 7, D-cycloserine not having any detectable effect on nocebo hyperalgesia is discussed from the perspective of subcortical NMDA receptor modulation. Because D-cycloserine seems to sometimes yield results in research on learned fear responses 62–66 but not always on other types of non-affective learning 67. It is thus possible to speculate that Dcycloserine may be more effective in modulating subcortical NMDA circuits engaged in paradigms with a heavier fear load 68. As such, our pharmacological experiment led us to speculate that the fear component reflected through findings in chapters 3, 5, and 7, could potentially be a secondary affective component that could modulate –but may not primarily underlie– nocebo hyperalgesic responses. While this is merely one speculation, further research specifically measuring fear levels is needed in order to understand the role of NMDA-dependent learning in nocebo hyperalgesia. Understanding the exact vulnerabilities caused by cooccurring affective and sensory processing is highly relevant for unravelling the etiology of persisting pain symptoms that are not fully explained by physical damage 59,61,69. The challenge of persisting pain symptoms lies in the multidimensional character of pain processing, influenced by previous experiences, beliefs, pain cognitions, as well as emotional factors, additionally to neurobiological factors directly related to sensory input 70,71. And while the cognitive and emotional literature on pain has yielded abundant evidence for their role in pain aggravation and chronification 61,72–75, the
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