Two PET Scan Studies of a Mu Opioid Agonist Drug
Agonist drugs activate receptors. Remifentinal is a synthetic opioid agonist that activates mu opioid receptors. It was given in clinically active dosages during two important pharmacological studies. The results of the first study suggest that both our higher-order endogenous opioid systems and our cognitive networks each participate not only in the way opioids relieve pain but also in the processes through which a placebo relieves pain.13
In this first controlled study, nine subjects received either a painfully hot stimulus (48°C) or merely a warm stimulus applied to the back of the left hand. During the painfully hot stimulus, the brain sites that responded included the insula bilaterally, the thalamus, and the caudal (back) portion of the anterior cingu-late cortex.
The next step was to observe what happened in the brain when an active, pharmacological dose of opioid drug was given intravenously (not a mere tracer dose). In this instance, remifentinal was given in one single, rapid injection. Not until the pain-relieving effect of this opioid had reached its peak did the anterior cingulate cortex show its greatest increase in activation. During this phase of optimum pain relief, which part increased? The increased activity occurred more in the rostral ( front) portion, not in the caudal portion of the cingulate. In humans, this rostral region is known to have a high concentration of opioid receptors. Interpretation: the opioid drug, acting on its receptors, had increased the activity of certain cells in the rostral anterior cingulate gyrus; this effect correlated with pain relief.
In parallel studies, tests were made of the same subjects' innate capacities to develop a placebo response. Some subjects derived much better pain relief from the inert placebo than did others. Which area became most active in their brains? Once again, the subjects who responded to the placebo with the best pain relief were those whose rostral part of the anterior cingulate gyrus became the most active site. In contrast, subjects who showed a low placebo response had lesser activity in this area.
What kind of local activity in this rostral anterior cingulate cortex might go on to help relieve pain? The authors suggested that activity in this particular region may have relayed some kind of pain relief message down to the central gray in the midbrain (see chapter 32) [Z:352-358].
One other region also increased its activity during the placebo response: the lateral part of the orbitofrontal cortex (see chapter 43). This finding raises another interesting possibility: perhaps we humans have access to a still higher collateral resource in the frontal lobe, one that would help to integrate several "coping" responses to relieve our sufferings and pain. In theory, when we develop such higher-level cognitive cues, they might act via relays from this lateral orbitofrontal region, which then go on down to reach those other descending pain-relief pathways that were outlined several sections above.
In greater detail, the theory would suggest that (1) by initiating a variety of "quasi-psychological" influences within parts of our frontal lobes, and (2) then by linking these cues with related activities arising in the front part of the anterior cingulate cortex, (3) we could next be able to relay messages downstream (to the thalamus or brainstem, or both), and (4) along the way, several endogenous opioids (and allied messengers) might be released which could finally help relieve pain and suffering [Z:352-354].
A caveat: these pioneering studies have resulted in intriguing interpretations that remain preliminary. We still need much more detailed information about the normal sequences and pathways that enable us to integrate and respond to pain signals.14 These cautionary remarks are especially relevant to the intricate circuitry that also enables us to release opioids on mu receptors at the higher cerebral levels. This topic is discussed in the paragraphs below.
A second PET study had a different goal. It was designed to monitor just the responses to remifentinal, with no added pain. In this instance, two different pharmacologically active doses of remifentinal were given. Each dose was infused slowly. Under these conditions, the pattern of brain responses to the opioid drug itself could be observed. Activities increased in many different regions. The opioid was followed by significant decreases of PET activity in both the inferior parietal lobes and in the left fusiform gyrus.15
The two separate PET scan studies just cited above focused on the way the brain responded during active doses of an opioid agonist drug. However, in the research next to be described, the subjects received only minute tracer doses of a mu agonist molecule. This research was designed both to locate and to measure those mu receptors that could just bind this tracer molecule. These investigators wished to avoid the sedation and other extraneous symptoms that are caused whenever higher, pharmacological doses of an opioid drug are given and strongly activate many mu receptors. Instead, they asked the question, Does the brain respond to pain by releasing its own opioids on these receptors? (But, one wonders, is it possible to eliminate from an experiment all the types of placebo responses that were cited earlier by Price and Soerensen? (see note 9.))
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