Mia Thomaidou

Chapter 7 – Pharmacological fMRI 221 Introduction Pain can arise as a debilitating symptom that is malleable and highly susceptible to an individual’s internal and external environment 1,2. Outcome expectations are shown to play a role in shaping pain responses to a given event or treatment 3–5. While positive outcome expectations can produce beneficial effects from inert treatments (placebo effects), negative outcome expectations can blunt the effect of active interventions and even increase pain sensitivity in response to inert treatments, a phenomenon termed nocebo hyperalgesia 6–9. An important process proposed to be involved in nocebo effects is associative learning 10–13. Classical conditioning is used in experimental nocebo models to form expectations through associative learning 11. In nocebo conditioning, negative associations form by pairing an inert nocebo stimulus (a sham treatment) to surreptitiously increased pain stimulations. After repeated trials, the nocebo stimulus evokes increases in perceived pain. Negative suggestions are commonly used to enhance conditioning 9,10,14. Concurrently, conditioned nocebo effects have been shown to effectively reduce using extinction paradigms in which learned associations are discontinued 14–16. One of the major neural components mediating associative learning processes are the N-methyl-D-aspartate (NMDA) receptors 17,18 whose agonism has been found to augment learning 19–22. Enhanced NMDA receptor activity promotes local neuroplasticity, which in turn is believed to enhance the acquisition and consolidation of learned material in both animals 23,24 and humans 25,26. Studies that used pharmacological agents such as D-cycloserine (DCS) to enhance NMDA-dependent learning support the implication of NMDA receptors in associative learning 27,28. DCS is a compound that impacts NMDA-mediated neuroplasticity

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