Learning decisively shapes the way individuals experience the world around them and how they respond to various external stimuli, including pain 1–3. Increased pain sensitivity can result from negative experiences creating negative expectations about an environmental stimulus, such as a treatment, a phenomenon termed nocebo hyperalgesia 1–3. Nocebo has been described as the negative counterpart to placebo. Nearly a century into the proliferation of placebo-controlled studies 4–6, research has shown that learned expectations regarding inert treatments may not only have positive placebo effects, but may also mimic negative treatment outcomes, such as medication side-effects 7–9. Nocebo responses may thus produce deleterious effects on a variety of symptoms, as a result of learning mechanisms that are not yet fully understood. For example, it remains unclear how negative expectations on a cognitive level influence pain processing in the brain, or what the involvement of relevant emotions may be. Due to a known involvement of learning in the experience of pain 1,10–12, it is important to study and better understand the biobehavioral mechanisms that underly nocebo hyperalgesia. In this general introduction, first, nocebo hyperalgesia will be framed as a multifaceted phenomenon that can be part of the intricate mechanisms of pain processing. Cognitive-emotional pain processing is described in the context of learned nocebo responses and as complimentary to sensory-discriminatory nociceptive processing. The state of the art in experimental nocebo research and the relevance of experimental learning mechanisms are then outlined. Experimental models that are typically implemented to investigate the cognitive and emotional aspects of nocebo hyperalgesia are described. Cognitive processes such as learning, as well as emotional processes such as fear, are then presented as major putative underlying factors in nocebo hyperalgesia, as indicated by experimental findings. Biobehavioral underpinnings of nocebo effects are then discussed in relation to current neurobiological literature; gaps in knowledge are highlighted. Finally, an outline of the current dissertation is presented.
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