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

Abstract

We investigated the mechanisms underlying the activation of endogenous opioids in placebo analgesia by using the model of human experimental ischemic arm pain. Different types of placebo analgesic responses were evoked by means of cognitive expectation cues, drug conditioning, or a combination of both. Drug conditioning was performed by means of either the opioid agonist morphine 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 produced placebo responses that were completely antagonized by naloxone. Morphine conditioning alone (without expectation cues) induced a naloxone-reversible placebo effect. By contrast, ketorolac conditioning together with expectation cues elicited a placebo effect that was blocked by naloxone only partially. Ketorolac conditioning alone produced placebo responses that were naloxone-insensitive. Therefore, we evoked different types of placebo responses that were either naloxone-reversible or partially naloxone-reversible or, otherwise, naloxone-insensitive, depending on the procedure used to evoke the placebo response. These findings show that cognitive factors and conditioning are balanced in different ways in placebo analgesia, and this balance is crucial for the activation of opioid or nonopioid systems. Expectation triggers endogenous opioids, whereas conditioning activates specific subsystems. In fact, if conditioning is performed with opioids, placebo analgesia is mediated via opioid receptors, if conditioning is performed with nonopioid drugs, other nonopioid mechanisms result to be involved.

Figures

Fig. 1.

Experimental paradigm used in the study to identify the opioid and nonopioid components of placebo analgesia. Below each group the experimental condition is specified. No treatment means that the tourniquet test was performed without infusion of any drug.

Fig. 2.

Analysis of the natural history of ischemic pain.A, Means and SDs of the natural history are shown for group 1 on 4 consecutive days. B, Pain baseline (mean ± SD) on day 1 in all groups and comparison with the natural history group on day 1. The horizontal bold linerepresents the mean of day 1 shown in A, thebroken lines represent the SD. The statistical analysis of the natural history is shown in Table 2.

Fig. 3.

Expectation-induced placebo analgesia and its blockade by naloxone. A, A hidden injection of naloxone on days 2 and 4 (group 2) does not produce any change in pain tolerance compared with days 1 and 3, indicating that naloxone per se does not affect this type of experimental pain. B, An open injection of saline (group 3) produces a placebo analgesic effect. Days 1 and 3 represent preinjection and postinjection controls.C, An open injection of naloxone on day 2 (group 4) blocks the placebo effect completely. In fact, pain tolerance on day 2 is equal to preinjection and postinjection controls.

Fig. 4.

A, After morphine conditioning on days 2 and 3, an open injection of saline, which is believed to be morphine (group 5), mimicks the morphine analgesic response.B, If an open injection of naloxone, which is believed to be morphine (group 6), is performed after 2 days of morphine conditioning, the morphine-mimicking effect is completely abolished.C, After morphine conditioning for 2 consecutive days, an open injection of saline, which is believed to be an antibiotic (group 7), mimicks the morphine response (albeit less than inA). D, An open injection of naloxone, which is believed to be an antibiotic (group 8), completely blocks the morphine-mimicking effect. In all cases, days 1 and 5 represent preconditioning and postconditioning controls.

Fig. 5.

Relationship between the analgesic response to morphine on day 3 and the placebo analgesic response on day 4. Eachcircle represents the response of a single subject. The responses are expressed as Δt, that is, the difference of pain tolerance between days 3 and 4 and day 1. A, In group 5 (black circles), the larger the morphine response, the larger the placebo response after a saline injection that is believed to be morphine. This correlation is completely disrupted by naloxone in group 6 (white circles). B, Same as inA but the saline injection is believed to be an antibiotic (groups 7 and 8).

Fig. 6.

A, After ketorolac conditioning on days 2 and 3, an open injection of saline that is believed to be ketorolac (group 9) mimicks the ketorolac analgesic response.B, An open injection of naloxone, which is believed to be ketorolac (group 10), blocks the ketorolac-mimicking effect only partially. C, After ketorolac conditioning for 2 consecutive days, an open injection of saline that is believed to be an antibiotic (group 11), mimicks the ketorolac response.D, An open injection of naloxone, which is believed to be an antibiotic (group 12), is ineffective in abolishing the ketorolac-mimicking effect. Preconditioning and postconditioning control tests are shown on days 1 and 5 in all cases.

Fig. 7.

Relationship between the analgesic response to ketorolac on day 3 and the placebo analgesic response on day 4. Eachcircle represents the response of a single subject. As in Figure 5, the responses are expressed as Δt, that is, the difference of pain tolerance between days 3 and 4 and day 1.A, In group 9 (black circles), the larger the ketorolac response, the larger the placebo response after a saline injection that is believed to be ketorolac. This correlation is maintained after naloxone injection in group 10 (white circles). B, Same as in A but the saline injection is believed to be an antibiotic (groups 11 and 12). In this case, naloxone is completely ineffective in disrupting the correlation.

Fig. 8.

Dissection of placebo analgesia into naloxone-reversible and naloxone-insensitive components.A, Expectation-induced placebo analgesia is completely blocked by naloxone. B, Morphine conditioning plus expectation produces a placebo response that is totally blocked by naloxone. Morphine conditioning alone induces placebo responses that, similarly, are completely blocked by naloxone. C, Nonopioid ketorolac conditioning plus expectation produces a placebo response that is only partially antagonized by naloxone. By contrast, nonopioid ketorolac conditioning alone induces placebo responses that are completely insensitive to naloxone.

Fig. 9.

Schematic diagram of the mechanisms activating endogenous opioid systems and nonopioid systems in placebo analgesia. The administration of a placebo can trigger both cognitive (expectation) and conditioning mechanisms. Expectation activates endogenous opioid systems, whereas conditioning is mediated by specific mechanisms. If conditioning is performed with opioids, placebo analgesia is mediated via opioid receptors. However, if conditioning is performed with nonopioid drugs, other mechanisms result to be involved. Therefore, placebo analgesia can result to be either naloxone-reversible or partially naloxone-reversible or, otherwise, naloxone-insensitive, depending on the procedure used to evoke the placebo response.