Neuropharmacological dissection of placebo analgesia: Expectation-activated opioid systems versus conditioning-activated specific subsystems

We investigated the mechanisms underlying the activation of endogenous opio ids in placebo analgesia by using the model of human experimental ischemic arm pain. Different types of placebo analgesic responses were evoked by mea ns of cognitive expectation cues, drug conditioning, or a combination of bo th. Drug conditioning was performed by means of either the opioid agonist m orphine hydrochloride or the nonopioid ketorolac tromethamine. Expectation cues produced placebo responses that were completely blocked by the opioid antagonist naloxone. Expectation cues together with morphine conditioning p roduced placebo responses that were completely antagonized by naloxone. Mor phine conditioning alone (without expectation cues) induced a naloxone-reve rsible placebo effect. By contrast, ketorolac conditioning together with ex pectation cues elicited a placebo effect that was blocked by naloxone only partially. Ketorolac conditioning alone produced placebo responses that wer e naloxone-insensitive. Therefore, we evoked different types of placebo res ponses that were either naloxone-reversible or partially naloxone-reversibl e or, otherwise, naloxone-insensitive, depending on the procedure used to e voke the placebo response. These findings show that cognitive factors and c onditioning are balanced in different ways in placebo analgesia, and this b alance is crucial for the activation of opioid or nonopioid systems. Expect ation triggers endogenous opioids, whereas conditioning activates specific subsystems. In fact, if conditioning is performed with opioids, placebo ana lgesia is mediated via opioid receptors, if conditioning is performed with nonopioid drugs, other nonopioid mechanisms result to be involved.