Despite the increasing research on
placebos in recent times, little is known about the nocebo effect, a phenomenon that is opposite to the placebo effect and whereby expectations of
symptom worsening play a crucial role. By studying experimental ischemic arm
pain in healthy volunteers and by using a neuropharmacological approach, we found that verbally induced nocebo
hyperalgesia was associated to hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, as assessed by means of
adrenocorticotropic hormone and
cortisol plasma concentrations. Both nocebo
hyperalgesia and HPA hyperactivity were antagonized by the
benzodiazepine diazepam, suggesting that anxiety played a major role in these effects. The administration of the mixed
cholecystokinin (CCK) type-A/B receptor antagonist
proglumide blocked nocebo
hyperalgesia completely but had no effect on HPA hyperactivity, which suggests a specific involvement of CCK in the hyperalgesic but not in the anxiety component of the nocebo effect. Importantly, both
diazepam and
proglumide did not show
analgesic properties on basal
pain, because they acted only on the nocebo-induced
pain increase. These data indicate a close relationship between anxiety and nocebo
hyperalgesia, in which the CCKergic systems play a key role in anxiety-induced
hyperalgesia. These results, together with previous findings showing that placebo
analgesia is mediated by endogenous
opioids, suggest that the
analgesic placebo/hyperalgesic nocebo phenomenon may involve the opposite activation of endogenous opioidergic and CCKergic systems.