Chapter 3 – Comprehensive review 99 underlying nocebo hyperalgesia. This implication of learning is important, particularly in light of evidence-based theories that show how the social environment and interpersonal experiences shape the experience of pain in healthy and patient populations 123–125. The specific learning correlates that are involved in nocebo effects have not been systematically manipulated and studied. Pharmacological and cognitive manipulations of learning are effective means in which learning has been studied in other fields of research 126,127. Yet, several important biochemicals relevant for pain and/or cognitive processes have not yet been studied. What future nocebo studies could attempt, is a direct manipulation of learning via, for example, agents that affect the nmethyl-d-aspartate receptor system such as amino acids 128. Alternatively, direct measures of learning ability (such as the Weschler Memory Scale;129 may shed light onto the specific learning mechanisms that are involved, and how individual differences related to learning may facilitate the formation of nocebo effects. It is imperative for future research to focus on precise learning mechanisms and comparisons between learning mechanisms in order to better understand and potentially therapeutically target the fundamental mechanisms by which nocebo hyperalgesia is induced. While some of the neurobiological correlates of nocebo effects are beginning to unravel, application of this knowledge in clinical contexts is also receiving increased attention. The studies reviewed in this article provide important insights into the key neurobiological mechanisms involved in nocebo effects. Notably, some of the neural correlates that have been linked to nocebo hyperalgesia are also implicated in chronic pain. For instance, data suggest that chronic pain involves brain structures such as the cingulate cortex and hippocampus may be associated with chronic stress and mesolimbic dopamine abnormalities that are involved in processing both nociceptive signaling and affective components of pain 20,74,130–132. Such overlapping neural factors may be crucial in the search for biomarkers of nocebo effects and identifying
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