The neurobiology of the placebo effect was born in 1978, when it was shown that placebo analgesia could be blocked by the opioid antagonist naloxone, which indicates an involvement of endogenous opioids (Levine et al., 1978
). By using this pharmacological approach with naloxone, several other studies have confirmed and extended this observation. For example, a placebo can reduce pain by both opioid and non-opioid mechanisms (Colloca and Benedetti, 2005) (Fig. 1). In the first case, placebo analgesia is typically blocked by the opioid antagonist naloxone, whereas in the second case it is not, depending on the procedure that is applied to induce the placebo analgesic response. In an experimental model of pain (Amanzio and Benedetti, 1999), the placebo response could be blocked by naloxone if it was induced by strong expectation cues, whereas if the expectation cues were reduced, it was insensitive to naloxone. In the same study, if the placebo response was obtained after exposure to opioid drugs, it was naloxone reversible, whereas if it was obtained after exposure to non-opioid drugs, it was naloxone insensitive. These data indicate that opioid and non-opioid mechanisms come into play under different circumstances. The placebo-activated endogenous opioid systems have been shown to have a somatotopic organization, because local naloxone-reversible placebo responses can be obtained in different parts of the body (Benedetti et al., 1999b).
On the basis of the anti-opioid action of cholecystokinin (CCK) (Benedetti, 1997), the CCK antagonist proglumide was found to enhance placebo analgesia through the potentiation of the placebo-activated opioid systems (Benedetti et al., 1995). Thus, the placebo analgesic response appears to result from a balance between endogenous opioids and endogenous CCK (Fig. 1). In one additional study in chronic pain patients, it was found that placebo responders showed higher concentration of endorphins in the CSF than placebo nonresponders (Lipman et al., 1990).
The placebo-activated endogenous opioids have also been shown to produce respiratory depression, a typical side effect of opioids. In fact, after repeated administrations of the opioid buprenorphine in the postoperative phase, which induces mild respiratory depression, a placebo is able to mimic the same respiratory depressant response, an effect that can be totally blocked by naloxone (Benedetti et al., 1999a). Therefore, not only do placebo-activated opioid systems act on pain mechanisms, but they act on the respiratory centers as well (Fig. 1). A recent study, in which the sympathetic control of the heart was analyzed during placebo analgesia, found that placebo analgesia was accompanied by a reduced heart rate and a decreased 
-adrenergic response, an effect that was reversed by naloxone, which indicates that opioid-mediated placebo analgesia also affects the cardiovascular system (Pollo et al., 2003) (Fig. 1).
In another recent study, some of the circumstances in which expectation and conditioning are involved have been suggested. In this study (Benedetti et al., 2003), the effects of opposing verbal suggestions on experimental ischemic arm pain in healthy volunteers and on motor performance in parkinsonian patients were analyzed. It was found that verbally induced expectations of analgesia/hyper-algesia and of motor improvement/worsening antagonized completely the effects of a conditioning procedure. In contrast, it was found that expectations of increase/decrease of growth hormone (GH) and cortisol did not have any effect on the secretion of these hormones. However, if a preconditioning was performed with sumatriptan, a 5-HT1B/1D agonist that stimulates GH and inhibits cortisol secretion, a significant increase of GH and decrease of cortisol plasma concentrations were found after placebo administration, although opposite verbal suggestions were given (Fig. 1). These findings suggest that expectations have no effect on hormonal secretion, although they affect pain and motor performance. This also provides some evidence that placebo responses are mediated by conditioning when unconscious physiological functions, such as hormonal secretion, are involved, whereas they are mediated by expectation when conscious physiological processes, such as pain and motor performance, come into play, although a conditioning procedure is performed. Thus, the placebo effect seems to be a phenomenon that can be learned either consciously or unconsciously, depending on the system that is involved (e.g., pain or hormone secretion).
The role of conditioning in the placebo effect is also shown by studies on the immune responses (Ader, 2003). For example, repeated associations between cyclosporin A (unconditioned stimulus) and a flavored drink (conditioned stimulus) induced conditioned immunosuppression in humans, in which the flavored drink alone produced a suppression of the immune functions, as assessed by means of interleukin-2 (IL-2) and interferon-
(IFN-) mRNA expression, in vitro release of IL-2 and IFN-, as well as lymphocyte proliferation (Goebel et al., 2002). This study supports a conditioning mechanism in immunosuppressive placebo responses and is in keeping with the effects of sumatriptan conditioning on GH and cortisol secretion (Benedetti et al., 2003).
It is worth pointing out that these placebo mechanisms have an important influence on the therapeutic outcome, and indeed they enhance the specific effect of a treatment. These additive effects have been demonstrated recently by studies that assessed treatment efficacy after the hidden administration of different therapies. In fact, the open administration of a treatment, in which the subject knows what is going on and expects an outcome, is more effective than a hidden one, in which the subject does not know that any therapy is being given and thus does not expect anything (Colloca et al., 2004). Likewise, the expected administration of a drug has a more powerful effect on brain metabolism than the unexpected administration (Volkow et al., 2003). These findings show that drug effects are reduced if expectations are absent and underscore how the knowledge about a treatment affects the therapeutic outcome.
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