Disruption of opioid-induced placebo responses by activation of cholecystokinin type-2 receptors

Rationale Placebos are known to induce analgesia through the activation of mu-opioid receptors in some circumstances, such as after morphine pre-conditioning, an effect that is blocked by opioid antagonists. Objectives On the basis of the anti-opioid action of cholecystokinin, here we tested whether the activation of the cholecystokinin type-2 receptors abolishes opioid-induced placebo responses. Methods The activation of the cholecystokinin type-2 receptors was performed by means of the agonist pentagastrin, and placebo responses were obtained after morphine preconditioning in an experimental human model of pain (tourniquet technique). Results Opioid-induced placebo responses were completely disrupted by pentagastrin administration. In addition, a high correlation between the response to morphine and the response to placebo was found, and this correlation was completely abolished by pentagastrin. Conclusion These results show that the cholecystokinin-2 receptor agonist, pentagastrin, has the same effect as the mu-opioid receptor antagonist, naloxone, on placebo analgesia induced by morphine pre-conditioning, which suggests that the balance between cholecystokinergic and opioidergic systems is crucial in placebo responsiveness in pain. These findings also suggest that cholecystokinin type-2 receptor hyperactivity might be present in placebo non-responders.