High opiate receptor binding potential in the human lateral pain system
Introduction
Endogenous opiates play a role in a multitude of bodily functions, including learning, memory, reward, eating, drinking, sexual activity, pregnancy, mood, locomotion, cardiovascular, gastrointestinal, renal and hepatic function, respiration, thermoregulation and immunological responses (Vaccarino and Kastin, 2001). The most common clinical use of opiates is, however, for their analgesic effects, which are mediated by inhibitory, mostly μ-opiate receptor (OR)-mediated effects in the peripheral nerve, the spinal cord, brainstem, thalamus and cortex. The highest opiate receptor density is in lamina II of the dorsal horn, i.e. in a nociceptive nucleus of the spinal cord. Opiate receptors are also present in other parts of the nociceptive system, including the periaqueductal gray, thalamus, anterior cingulate cortex and insula (Yaksh et al., 1988, Jones et al., 1991, Casey et al., 2000, Bencherif et al., 2002); these opiate receptors can be mapped by positron emission tomography (PET). Early PET studies (Jones et al., 1991, Vogt et al., 1995b) reported that the primary somatosensory cortex (SI), a part of the lateral pain system, has one of the lowest opiate receptors densities and that opiate receptors are primarily associated with the medial pain system (medial thalamus, anterior cingulate cortex) that is thought to mediate the affective–motivational component in pain perception (Melzack and Casey, 1968, Rainville et al., 1997, Treede et al., 1999, Price, 2000).
Concepts of the role of the anterior cingulate cortex and other cortical structures in pain perception have evolved over the past decade. What was formerly summarily termed anterior cingulate cortex has been functionally divided into a more posterior motor part called midcingulate cortex (MCC) and the ACC proper in the perigenual region (Vogt et al., 1995a), with higher opiate receptor density than MCC both in rats and in humans (Vogt et al., 1995b, Vogt et al., 2001). As part of the lateral system, the region around the Sylvian fissure contains several nociceptive regions, including SII in the parietal operculum, medial parts of the frontal operculum and anterior as well as dorsal aspects of the insula (Treede et al., 2000, Craig, 2002, Frot and Mauguière, 2003). While the insula was traditionally considered to be part of the medial pain system due to its output into the limbic system, it receives direct nociceptive input from lateral thalamic nuclei (Apkarian and Shi, 1994) and may thus also be seen as part of the lateral pain system. The operculo-insular cortex (OIC) has one of the shortest latencies of activation by painful stimuli (Frot and Mauguière, 2003, Schlereth et al., 2003).
Little is known about opiate receptor distribution in the OIC. The insula has a high density (Atweh and Kuhar, 1977, Pfeiffer et al., 1982, Jones et al., 1991), but the frontoparietal operculum has not been studied as a separate area in its own right. We now set out to use PET imaging with the subtype-unselective opioid receptor ligand [18F]Fluoroethyl-diprenorphine ([18F]FEDPN, Wester et al., 2000) coregistered with structural MRI to perform a region of interest analysis of opiate receptor availability in nociceptive cortex regions. We compared these regions with regions known for high (thalamus, basal ganglia) or low (SI/MI, occipital cortex) opiate receptor density.
Section snippets
Methods
This study was carried out in accordance with the Helsinki Declaration and was approved by the local ethics committee, the German Federal Health Administration (BfArM) and the German radiation protection authorities (BfS). Informed written consent was obtained from each subject.
Results
High [18F]FEDPN binding was seen in the thalamus, the basal ganglia (caudate, putamen) and further lateral, the insula (Fig. 2). The regions with the lowest opiate receptor availability were the occipital cortex (transverse slice), which was used as reference region, and the sensory–motor strip around the central sulcus (sagittal slice). The sagittal slice demonstrates that, within the insula, opiate receptors are mostly located in its anterior and dorsal parts. The dorsal insula is immediately
Discussion
To date, the lateral pain system, including the primary and secondary somatosensory cortex (SI, SII), has been considered to be an area of low opioid receptor density, whereas structures of the medial system, like medial thalamus and cingulate cortex, are known to have a much higher opioid receptor density. In this PET study in a sample of healthy subjects, we calculated the opioid receptor BP in 11 bilateral regions of interest (ROIs), each of which was assigned on the individual MR scan of
Conclusions
The present study shows that the operculo-insular cortex, a part of the lateral pain system, has high opiate receptor density of similar magnitude as the anterior and midcingulate cortex of the medial pain system. These data suggest that in addition to the affective–motivational pain component also the sensory-discriminative pain component may be influenced by opiate receptor agonists at a cortical level. Furthermore, our factor analysis data suggest that the operculo-insular cortex forms a
Acknowledgments
This study was supported by the Deutsche Forschungsgemeinschaft (Tr 236/13-3), DFNS (01EM0506) and Stiftung Rheinland-Pfalz. This paper contains essential parts of the doctoral thesis of A. Bellosevich to be submitted to the Medical Faculty of the Johannes Gutenberg-University Mainz, Germany.
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