Response: Measuring our natural painkiller

We appreciate very much Stuart Derbyshire's thoughtful commentary and review of our manuscript and related literature. Indeed, we agree that much remains to be learned about the physiological mechanisms involved in the experience of pain, at the level of both its representation and its modulation. As we further understand the circuitry involved in the processing of various components of the pain experience (i.e. anticipatory, affective, sensory and cognitive), the examination of the neurotransmitter and receptor systems modulating these phenomena appears to be a logical ‘next step’. This information might eventually allow further integration of human research data with that acquired using pharmacological and molecular biological techniques in basic animal models. Hopefully, this will ultimately lead to the delineation of potential targets for pharmacological interventions.Derbyshire also focused on the brain regions found involved in the representation and μ-opioid receptor-mediated suppression of pain affect. μ-Opioid receptor activation by endogenous opioids at the level of the dorsal anterior cingulate, nucleus accumbens and thalamus was found to reduce the affective ratings of the pain experience. Among those regions, involvement of thalamic μ-opioid receptors would be expected, both based on preclinical findings [1xAntinociceptive effects of morphine injected into the nucleus parafascicularis thalami of the rat. Harte, S. et al. Brain Res. 2000; 874: 78–86Crossref | PubMed | Scopus (31)See all References[1] and by virtue of its extensive projections to prefrontal and anterior cingulate cortical fields. In the anterior cingulate, μ-opioid receptor activation was observed in anterior and more dorsal regions, but only the dorsal anterior cingulate activation was found correlated with the suppression of pain affect as rated by the McGill Pain Questionnaire. As Derbyshire notes, the location of this effect was posterior to that observed by Rainville et al. [2xPain affect encoded in human anterior cingulate but not somatosensory cortex. Rainville, P. et al. Science. 1997; 277: 968–971Crossref | PubMed | Scopus (1514)See all References[2] in their work on pain unpleasantness.Possible explanations for this discrepant finding might center both on the type of pain stimulus utilized and on the specific measures of pain affect. For example, Rainville et al. [2xPain affect encoded in human anterior cingulate but not somatosensory cortex. Rainville, P. et al. Science. 1997; 277: 968–971Crossref | PubMed | Scopus (1514)See all References[2] utilized a relatively short painful stimulus (heat pain for 75 s). A subsequent manuscript by Tolle et al. [3xRegion-specific encoding of sensory and affective components of pain in the human brain: a positron emission tomography correlation analysis. Tolle, T. et al. Ann. Neurol. 1999; 45: 40–47Crossref | PubMed | Scopus (265)See all References[3] reported findings using a longer duration of pain (5 min heat pain). Their results showed that ratings of pain unpleasantness correlated with the degree of activation in the dorsal anterior cingulate. After adjustment for the coordinate system utilized (International Conference on Brain Mapping or Talairach and Tournoux coordinates), the area implicated in pain affect representation in the latter report appears to be more closely related to that found regulated by endogenous opioids in our data. Of note, we utilized a model of pain of much longer duration than the two previous reports (20 min). In view of these findings, it is tempting to speculate that different forms of pain (short versus sustained duration) might be represented and regulated in different regions of the anterior cingulate cortex. Dorsal regions of the anterior cingulate have been implicated in cognitive and higher order associative processing [4xCognitive and emotional influences in anterior cingulate cortex. Bush, G. et al. Trends Cognit. Sci. 2000; 4: 215–222Abstract | Full Text | Full Text PDF | PubMed | Scopus (3182)See all References[4]. As pain becomes more sustained, it is possible that further cognitive operations could become engaged in the processing of the affective component of the pain experience. In turn, different rating scales (pain affect in the McGill Pain Questionnaire, visual analog scales of unpleasantness) could reflect these cognitive processes to a different extent, leading to differences in the regional distribution of the effects observed.As noted by Derbyshire, and several authors before us, the experience of pain is highly complex. Certainly, further development and investment in the field is necessary to fully understand its components and their implications for human physiological and pathological states.