The role of NMDA receptor-dependent learning in the induction of nocebo hyperalgesia

This study aimed to create a better understanding of the neurobiological mechanisms underlying the induction of nocebo hyperalgesia. Nocebo hyperalgesia refers to an increased pain perception resulting from negative outcome expectations, a phenomenon that can negatively influence a patient’s clinical outcome. Much concerning the mechanisms underlying the induction of nocebo hyperalgesia is still unknown, although it can be hypothesized that NMDA receptor-dependent learning may play a role. The current study tested this hypothesis by pharmacologically manipulating NMDA receptor- dependent learning in healthy participants, expecting that the pharmacological manipulation would facilitate the induction of nocebo hyperalgesia. Participants (n = 50) received either a placebo or an 80 mg dose of D-cycloserine (DCS), a partial NMDA receptor agonist. Nocebo hyperalgesia was induced in both groups with verbal suggestions and a classical conditioning paradigm consisting of an induction and...Show moreThis study aimed to create a better understanding of the neurobiological mechanisms underlying the induction of nocebo hyperalgesia. Nocebo hyperalgesia refers to an increased pain perception resulting from negative outcome expectations, a phenomenon that can negatively influence a patient’s clinical outcome. Much concerning the mechanisms underlying the induction of nocebo hyperalgesia is still unknown, although it can be hypothesized that NMDA receptor-dependent learning may play a role. The current study tested this hypothesis by pharmacologically manipulating NMDA receptor- dependent learning in healthy participants, expecting that the pharmacological manipulation would facilitate the induction of nocebo hyperalgesia. Participants (n = 50) received either a placebo or an 80 mg dose of D-cycloserine (DCS), a partial NMDA receptor agonist. Nocebo hyperalgesia was induced in both groups with verbal suggestions and a classical conditioning paradigm consisting of an induction and evocation phase. In the induction phase, high intensity heat-pain stimuli were given during trials where a sham electrical stimulation device was supposedly turned on (nocebo trials), while moderate heat-pain stimuli were given during trials where a sham electrical stimulation device was supposedly turned off (control trials). During the evocation phase, only moderate pain stimuli were given. Nocebo hyperalgesia was indicated when participants rated their pain higher during nocebo trials compared to control trials. A significant paired-samples t-test (t (49) = -8.55, p < .001) suggested that nocebo hyperalgesia was successfully induced in both groups, further confirming that nocebo hyperalgesia can be induced by classical conditioning and verbal suggestions. Nevertheless, the pharmacological manipulation of NMDA receptor-dependent learning with 80 mg DCS did not facilitate the magnitude of the induced nocebo hyperalgesia more than a placebo, as indicated by a one-way ANOVA (F (1, 49) = 0.028, p = 0.867). The usability of DCS in nocebo research was discussed, and further research was recommended. It is important that the current study is replicated, possibly with the use of another glutamatergic agent. The results from future studies could play a significant role in diminishing the impact of nocebo hyperalgesia on clinical practice.Show less

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The role of NMDA receptor-dependent learning in the induction of nocebo hyperalgesia