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Psychopharmacology (Berl). 2011 Feb;213(4):791-7. doi: 10.1007/s00213-010-2037-y. Epub 2010 Oct 8.

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

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Department of Neuroscience, University of Turin Medical School and National Institute of Neuroscience (INN), Turin, Italy.



Placebos are known to induce analgesia through the activation of μ-opioid receptors in some circumstances, such as after morphine pre-conditioning, an effect that is blocked by opioid antagonists.


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.


The activation of the cholecystokinin type-2 receptors was performed by means of the agonist pentagastrin, and placebo responses were obtained after morphine pre-conditioning in an experimental human model of pain (tourniquet technique).


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.


These results show that the cholecystokinin-2 receptor agonist, pentagastrin, has the same effect as the μ-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.

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