Chapter 1 – General introduction 13 stimulus and the worsening of pain is formed and the nocebo stimulus can evoke changes in perceived pain (conditioned response, CR), similar to the previous pain stimulus (Figure 1) 35,36. The powerful associative learning mechanisms employed by classical conditioning serve to recreate learned hyperalgesic responses to a specific stimulus. Classical conditioning thus attempts to recreate a putative clinical context in which not only physical injury but also memories of previous experiences and expectations about the future could have a strong impact on pain symptoms. Verbally delivered negative information can also alter pain expectations through instructional learning. Negative suggestions typically involve explaining the pain-enhancing effect of a (sham) treatment. Suggestions are used to induce nocebo hyperalgesia by themselves or to enhance the effectiveness of nocebo conditioning 9,37,38. The combination of conditioning and verbal suggestions is found to create the strongest experimental model of nocebo hyperalgesia 7,39. This points towards a complex interplay of diverse learning processes that may underlie nocebo effects. Experimental models are thus suited for examining pain aggravation under nocebo hyperalgesic conditions, but they can also shed light on pain chronification due to nocebo. Experimental attenuation models of conditioned effects have shown that learning may be involved in the persistence of pain over time. Paradigms that employ extinction or counterconditioning methods may provide valuable insights into the factors that contribute to nocebo responses 40–43. In a typical extinction paradigm, associations between the UCS and CS are discontinued, and learned effects would be expected to become extinct over multiple trials that are no longer negatively reinforced 7,39. This type of behavioral paradigm represents that, even classical conditioning has been discontinued, increased pain sensitivity can persist in response to a learned nocebo stimulus, over a prolonged period of extinction 42,44. The
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