Somatotopic activation of opioid systems by target-directed expectations of analgesia

Abstract

We induced specific expectations of analgesia on four different parts of the body to understand how endogenous opioid systems are activated by expectancies. The left hand, right hand, left foot, and right foot were simultaneously stimulated by means of a subcutaneous injection of capsaicin, which produces a painful burning sensation. Specific expectations of analgesia were induced by applying a placebo cream on one of these body parts and by telling the subjects that it was a powerful local anesthetic. In such a way, expectancy of the anesthetic effect was directed only toward the part on which the placebo cream was applied. We found that a placebo analgesic response occurred only on the treated part, whereas no variation in pain sensitivity was found on the untreated parts. If the same experiment was performed after an intravenous infusion of the opioid antagonist naloxone, this highly spatial-specific placebo response was totally abolished, indicating that it was completely mediated by endogenous opioid systems. These findings show that a spatially directed expectation of pain reduction is capable of inducing a specific effect only on the part of the body which is the target of the expectation. Most important, this specific effect is mediated by endogenous opioids, indicating that placebo-activated opioids do not act on the entire body but only on the part where expectancy is directed. This suggests that a highly organized and somatotopic network of endogenous opioids links expectation, attention, and body schema.

Fig. 1.

Experimental setup. Four subcutaneous needles, which are filled with capsaicin, are inserted under the skin of the dorsal side of both hands and both feet and connected to an infusion pump. The four electrodes are used to signal on which part of the body the subjects had to focus their attention and to judge capsaicin pain intensity. Naloxone was administered through the intravenous line.

Fig. 2.

Experimental design. Starting from time 0, the same design was used for all 173 subjects. In contrast, they were subdivided into six groups that received different treatments at 15 and 10 min before time 0.

Fig. 3.

Data from three representative subjects in polar coordinate systems. The subject in A belongs to the natural history group; thus, he did not receive any treatment. The four quadrants represent the four different parts of the body. For each quadrant, the pain time course is shown in which the distance from the center represents pain intensity and the angular coordinates represent the minutes after capsaicin injection. The first minute after capsaicin injection is shown for each quadrant. The subject in Bwas treated with a placebo cream on the left hand (underlined), so that expectation of analgesia was directed to the left hand. Accordingly, a placebo pain reduction occurred specifically on the left hand. The subject in Cwas treated with a placebo cream on the right hand and left foot (underlined), so that expectation of analgesia was directed to the right hand and left foot. Accordingly, a placebo pain reduction occurred specifically on the right hand and left foot.

Fig. 4.

A, Natural history of the pain induced by capsaicin on the hands and feet. B, Same as in A, but these subjects received a hidden injection of naloxone. Note that naloxone did not affect the time course of pain. The statistical analysis of the areas under the curve is shown in Table2.

Fig. 5.

The effects of the application of a placebo cream on the left hand. The specific expectation of analgesia on the left hand produced a placebo effect only on the left hand and not on the other parts of the body (A). This highly specific placebo effect was completely blocked by naloxone (B). The broken lines show the natural histories of Figure 4A. The statistical analysis of the areas under the curve is shown in Table 3.

Fig. 6.

The effects of the application of a placebo cream on the right hand and left foot. The specific expectations of analgesia on the hand and foot produced specific placebo effects on the right hand and left foot, whereas the other two parts of the body were unaffected (A). These specific placebo effects were completely blocked by naloxone (B). Thebroken lines show the natural histories of Figure4A. The statistical analysis of the areas under the curve is shown in Table 4.

Fig. 7.

Percent of preinjection control pain threshold at 30 and 120 min after capsaicin injection in all experimental groups. No significant differences can be observed in A,B, D, and F. In contrast, in C and E, the black columns represent those parts of the body where the placebo cream was applied and where pain thresholds result to be significantly higher compared with the other parts of the body. LH, Left hand; RH, right hand; LF, left foot;RF, right foot.

Fig. 8.

Model explaining the findings of the present study. Spatial-specific expectations of analgesia produce opioid-mediated placebo effects only on those parts where expectations are directed. To do this, specific expectations activate specific opioid subsystems which, in turn, interact with specific topographic representations of the body. This model implies that placebo-activated endogenous opioids are not released throughout the nervous system but are arranged in a highly organized network, linking expectancies, attention, and body schema. +, Excitation; −, inhibition.