Chapter 1 – General introduction 15 plasticity processes, including learning by association 53–54. Pharmacological manipulation of these receptors has been proven fruitful for enhancing learning during exposure therapy 53–55 and may also prove useful in the examination of the precise neurocognitive mechanisms, such as specific receptors and localized learning processes, that may facilitate nocebo hyperalgesia. Emotional underlying factors, such as fear of pain symptoms, may additionally tie into the processing of pain based on prior experiences and expectations. Through the common theme of learning, nocebo hyperalgesia bares some similarities to the formation of phobias 56–58. Nocebo and phobic responses may both be characterized by a key involvement of cognitive-affective components such as aversive learning and fear of a stimulus 12,53,59. Indeed, neural correlates of nocebo hyperalgesia show some involvement of fear processing. This is especially evident by the consistent involvement of the amygdala in both nocebo responses 19,20,60 and fear responses 61–64. Similarly to nocebo conditioning, pain-related fear can be acquired through associative learning 65–68. Pain-related fear may thus be relevant to nocebo effects because it may arise in experimental models as a result of experienced pain or as a result of threatening information regarding upcoming pain. Fear experienced during nocebo conditioning may thus potentially augment the acquisition of negative expectations, but experimental studies on this are lacking so far. This makes fear an especially important factor to study in relation to nocebo hyperalgesia.
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