A PET [¹⁸F]altanserin study of 5-HT_2A receptor binding in the human brain and responses to painful heat stimulation

Abstract

There is a large body of evidence that serotonin [5-hydroxytryptamine (5-HT)] plays an important role in the transmission and regulation of pain. Here we used positron emission tomography (PET) to study the relationship between baseline 5-HT_2A binding in the brain and responses to noxious heat stimulation in a group of young healthy volunteers. Twenty-one healthy subjects underwent PET scanning with the 5-HT_2A antagonist, [¹⁸F]altanserin. In addition, participants underwent a battery of pain tests using noxious heat stimulation to assess pain threshold, pain tolerance and response to short-lasting phasic and long-lasting (7-minute) tonic painful stimulation. Significant positive correlations were found between tonic pain ratings and [¹⁸F]altanserin binding in orbitofrontal (r = 0.66; p = 0.005), medial inferior frontal (r = 0.60; p = 0.014), primary sensory–motor (r = 0.61; p = 0.012) and posterior cingulate (r = 0.63; p = 0.009) cortices. In contrast, measures of regional [¹⁸F]altanserin binding did not correlate with pain threshold, pain tolerance, or suprathreshold phasic pain responses. These data suggest that cortical 5-HT_2A receptor availability co-varies with responses to tonic pain. The correlation between [¹⁸F]altanserin binding in prefrontal cortex and tonic pain suggests a possible role of this brain region in the modulation and/or cognitive-evaluative appreciation of pain.

Introduction

There is a large body of evidence for the involvement of serotonin [5-hydroxytryptamine (5-HT)] in pain processing and pain modulation. Studies have shown that 5-HT modulates nociceptive processing at several levels of the neuraxis, proceeding from the sensory nerves in the periphery to the spinal cord, and to loci in the brain. The role of 5-HT in pain processing is consequently complex; there is strong evidence that 5-HT has both pronociceptive and antinociceptive actions at the level of the spinal cord dorsal horn. This bivalent action is mediated through descending projections in the dorsolateral funiculus originating in the rostroventromedial medulla (Millan, 2002 for a review). Major 5-HT pathways in the CNS arise from the raphe nuclei, from which the major descending pain modulatory pathways originate. Other serotonin pathways arise from the medullary, pontine and mesencephalic reticular formation which innervate an extensive (sub)cortical network, including the thalamus, basal ganglia, anterior cingulate cortex (ACC) and prefrontal cortex, amygdala and hippocampus. Thus, 5-HT pathways occupy a highly strategic position to regulate pain processing.

There is evidence from animal studies that 5-HT_2A receptors play an important role in pain processing (Bardin et al., 2000, Honda et al., 2006 Kjørsvik et al., 2001, Okamoto et al., 2007, Soleimannejad et al., 2006, Van Steenwinckel et al., 2007). Recent studies in knock-out mice showed that the 5-HT_2A receptor system modulates pain responses in the late phase of the formalin pain test, in which the behavioral response to an aversive injection in the paw pad is observed. In contrast, the 5-HT_2A receptor system did not affect either acute mechanical and thermal pain or the pain response in the acute phase of the formalin test (Kayser et al., 2007).

There is a surprising lack of studies relating the cerebral 5-HT systems to pain processing in human brain. So far, only a single PET study in human volunteers has examined possible correlations between 5-HT receptor binding and pain responsiveness (Martikainen et al., 2007). In this study, the availability of the 5-HT_1A receptors was investigated using the PET tracer [¹¹C]WAY-100635. The authors reported negative correlations between pain intensity ratings on the cold pressor test and 5-HT_1A binding potential (BP_P) in a global pattern including prefrontal cortex, insula, posterior cingulate cortex (PCC), amygdala, and dorsal raphe nucleus. Increases in cold pressor pain threshold evoked by a painful conditioning stimulus were positively correlated with 5-HT_1A BP_P in amygdala and medial prefrontal cortex. Together these data show that a high availability of 5-HT_1A receptors is associated with low pain ratings and with an elevated capacity for central suppression of pain.

In this study we investigate the purported role of the 5-HT_2A receptor system in pain processing. Based on preclinical findings, reviewed above, we tested the hypothesis that 5-HT_2A receptor availability would correlate with measures of tonic but not of phasic pain. In particular, we measured pain responses in a group of young healthy volunteers who had undergone PET examinations with the 5-HT_2A selective PET tracer [¹⁸F]altanserin.