As described above, substantial evidence implicates the endogenous opioid system in the mediation of placebo effects under conditions of expectation of analgesia. During both clinical and experimentally induced pain, placebo administration with expectation of analgesia has been associated with reductions in pain ratings that were reversed by either the open or hidden administration of naloxone (i.e., they were mediated by the activation of pain-suppressive endogenous opioid neurotransmission) (Gracely et al., 1983
; Grevert et al., 1983; Levine and Gordon, 1984; Benedetti, 1996; Amanzio and Benedetti, 1999). Nonopioid mechanisms have also been described, particularly in the context of previous preconditioning with non-opioid agents (Amanzio and Benedetti, 1999).
In an initial examination of the neuronal circuitry implicated in these mechanisms, Petrovic et al. (2002) described a coincidence of increases in regional cerebral blood flow (CBF) by the systemic administration of a µ-opioid receptor agonist, remifentanil, and placebo with expectation of analgesia in the rostral anterior cingulate cortex. Furthermore, individuals who were placebo responders showed more pronounced rostral anterior cingulate regional blood flow responses to remifentanil. These data then suggested the presence of variations in the responses of the µ-opioid receptor system as a function of placebo response, localized in the rostral anterior cingulate.
Regarding the circuitry implicated in placebo analgesia (and as described in more detail below in Functional neuroanatomy of placebo analgesia), Wager et al. (2004) used functional magnetic resonance imaging (fMRI) to indirectly measure neuronal activity during the administration of a placebo with expectation of analgesia. Placebo administration was associated with reductions in the activity of pain-responsive regions while subjects underwent a painful heat stimulus. The regions involved included the rostral anterior cingulate, the insular cortex, and the thalamus. This study used an expectancy manipulation to elicit a placebo response, which enhances belief in the placebo. This procedure does not involve classical conditioning per se (because there is no active unconditioned stimulus), which has been associated with non-opioid-mediated analgesic mechanisms (Amanzio and Benedetti, 1999). Although the methodology used does not examine the neurochemical mechanisms inducing the placebo analgesic effect, the regions implicated do present high concentrations of µ-opioid receptors and demonstrate increases in regional blood flow after the exogenous administration of µ-opioid receptor agonists (Firestone et al., 1996; Adler et al., 1997; Schlaepfer et al., 1998; Casey et al., 2000; Wagner et al., 2001).
The endogenous opioid system, and specifically its activation of µ-opioid receptors, thought to primarily mediate the observed effects of placebo and naloxone, as noted above, is additionally implicated in a number of other functions. These range from the regulation of central stress responses and pain, hypothalamic-pituitary regulation of reproductive and stress hormones (e.g., ACTH and the immunologically active cortisol), and the adaptation and response to novel and emotionally salient stimuli (Watkins and Mayer, 1982; Akil et al., 1984; Kalin et al., 1988; Rubinstein et al., 1996; Sora et al., 1997; Nelson and Panksepp, 1998; Smith et al., 1998; Filliol et al., 2000; Drolet et al., 2001; Zubieta et al., 2001, 2003a; Moles et al., 2004). It therefore has the potential to affect not only placebo-induced analgesic effects but also a number of other physiological functions.
A recent study (Zubieta et al., 2005a) directly examined whether the introduction of a placebo with expectation of analgesia activates endogenous opioid neurotransmission, using PET and a µ-opioid receptor-selective radiotracer. Under these conditions, activation of this neurotransmitter system is evidenced by reductions in the in vivo availability of synaptic µ-opioid receptors to bind the radiolabeled tracer (Zubieta et al., 2001, 2002, 2003b; Bencherif et al., 2002).
The activation of the endogenous opioid system and µ-opioid receptors was compared between sustained pain and sustained pain plus placebo conditions in a sample of 14 healthy males, aged 20-30 years. Significantly higher levels of activation were obtained for the condition in which placebo was administered. After correction for multiple comparisons, statistically significant effects of placebo on µ-opioid system activation were obtained in the left (ipsilateral to pain) dorsolateral prefrontal cortex (DLPFC) [at Brodmann areas (BA) 8 and 9], pregenual rostral right (contralateral) anterior cingulate (BA 24 and 25), right (contralateral) anterior insular cortex, and left (ipsilateral) nucleus accumbens (Fig. 3). A second area within the contralateral insular cortex, in its posterior region, also showed changes in neurotransmission, but it no longer reached statistical significance after correction for multiple comparisons (Fig. 3).
The psychophysical correlates associated with the placebo-induced activation of the endogenous opioid system were then examined. For these correlates, subjects were selected who showed a substantial placebo effect (i.e., >10% change in the in vivo availability of µ-opioid receptors after placebo administration). This threshold was selected as exceeding the typical interexperimental variability in PET µ-opioid receptor measurements (Zubieta et al., 2005a). In the pregenual anterior cingulate, placebo-induced µ-opioid system activation above those levels was significantly correlated with ratings of visual analog (VAS) pain intensity and pain unpleasantness, McGill Pain Questionnaire (MPQ) sensory subscale scores, and total MPQ scores. Placebo-induced activation of endogenous opioid neurotransmission in this region was also highly and positively correlated with a measure of pain tolerance.
In the right anterior insular cortex, significant correlations were obtained with the changes in VAS ratings of pain intensity and MPQ sensory and total MPQ scores. At the level of the left nucleus accumbens, significant correlations were obtained, in the same direction, with the change in VAS pain intensity ratings, MPQ affective subscale, and reductions in negative affect scores experienced during the challenge (Profile of Mood Scale). In the left dorsolateral prefrontal cortex, µ-opioid system activation was negatively correlated with the expected analgesic effect as rated by the subjects before placebo administration.
The regions in which placebo administration increased the endogenous opioid neurotransmission primarily coincided with that observed by Wager et al. (2004) as reductions in pain-induced metabolic demands as measured by fMRI during placebo administration (i.e., prefrontal cortex, pregenual anterior cingulate, and insular cortex). The regions implicated in the placebo analgesic effect were part of those in which prominent endogenous opioid neurotransmission and µ-opioid receptor populations are present in humans (Gross-Isseroff et al., 1990; Gabilondo et al., 1995). The rostral anterior cingulate had also been noted to be more prominently activated in high placebo responders after µ-opioid agonist administration (Petrovic et al., 2002).
This work takes the investigation of placebo effects directly into the realm of human brain neurotransmission, addressing the effects of cognitive expectations on neural chemical functions. The results presented are consistent with reports implicating the endogenous opioid system in the mediation of placebo analgesic effects, previously examined by their blockade after the systemic administration of naloxone (Gracely et al., 1983; Grevert et al., 1983; Levine and Gordon, 1984; Benedetti, 1996; Amanzio and Benedetti, 1999).
Examination of the individual data also highlighted that changes in neurochemical signaling induced by the introduction of a placebo did not represent an on-off phenomenon but rather a graded effect that was influenced, with relative independence, by a number of brain regions with complex "integrative-motivational" functions. For example, some subjects presented with profound neurochemical responses to the placebo intervention in some but not other regions (Fig. 4). Multiple regression analyses were then conducted to examine whether individual differences in the pain experience (i.e., the analgesic placebo effect serves an adaptive function in the face of increased needs to reduce the individual experience of pain) could be driving some of the variations in the neurochemical response to the placebo. A multiple regression model that included sensory and affective qualities of pain, a measure of pain sensitivity, and the internal affective state of the volunteers during pain (in the absence of placebo) described 40-65% of the variance in the subsequent regional neurochemical responses to placebo. When the individual items in the model were examined, the internal affective state of the volunteers during pain (as measured with the Positive and Negative Affectivity Scale) and the affective quality of the pain (as measured with the MPQ pain affect subscale) were the only items reaching statistically significant correlations with regional endogenous opioid release after placebo administration. This was the case in the dorsolateral prefrontal cortex, pregenual anterior cingulate, anterior insular cortex, and nucleus accumbens (Zubieta et al., 2005b).
The studies and analyses presented above demonstrate that expectation of analgesia is an important factor in the engagement of objective, neurochemical antinociceptive responses to a placebo and, furthermore, that these processes appear to involve the expectations of the perceived analgesic efficacy of the placebo, an effect that is mediated by endogenous opioid neurotransmission in the dorsolateral prefrontal cortex. However, a substantial proportion of the variance in the regional neurochemistry of placebo analgesia was explained by the experience of pain itself. In this regard, variations in pain sensitivity, in the affective qualities of the pain, as well as the internal affective state of the individual during pain explained a substantial proportion of the variance in the formation of the placebo analgesic effect. These findings seem to support the concept that placebo responses form part of adaptive mechanisms engaged as a function of the perceived needs of the organism, with modifiers, such as negative affective states, further regulating those responses. They also suggest that the study and understanding of individual variations in placebo responses is further complicated by the individual responses to the process (e.g., clinical pain) for which relief is expected.
These data are additionally consistent with the notion that placebo-responding regions and neurochemical systems (e.g., the endogenous opioid system and µ-opioid receptors) are an intrinsic part of neuronal processes that mediate the interaction between positive environmental conditions (in the present case the suggestion of analgesia) and the corresponding physical and emotional responses of the individual. From a different perspective, disruptions in the function of these normal regulatory processes [e.g., dorsolateral prefrontal atrophy in chronic pain patients (Apkarian et al., 2004)] may explain the typically lower rates of placebo responding in the more persistent or severe forms of various illnesses. These may further represent points of vulnerability for the expression or maintenance of various pathological states.
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