Abstract
The neurotransmitter serotonin, involved in the regulation of pain and emotion, is critically regulated by the 5‐HT1A autoreceptor and the serotonin transporter (5-HTT). Polymorphisms of these genes affect mood and endogenous pain modulation, both demonstrated to be altered in fibromyalgia subjects (FMS). Here, we tested the effects of genetic variants of the 5‐HT1A receptor (CC/G-carriers) and 5-HTT (high/intermediate/low expression) on mood, pain sensitivity, cerebral processing of evoked pain (functional MRI) and concentrations of GABA and glutamate (MR spectroscopy) in rostral anterior cingulate cortex (rACC) and thalamus in FMS and healthy controls (HC). Interactions between serotonin-relevant genes were found in affective characteristics, with genetically inferred high serotonergic signalling (5-HT1A CC/5-HTThigh genotypes) being more favourable across groups. Additionally, 5‐HT1A CC homozygotes displayed higher pain thresholds than G-carriers in HC but not in FMS. Cerebral processing of evoked pressure pain differed between groups in thalamus with HC showing more deactivation than FMS, but was not influenced by serotonin-relevant genotypes. In thalamus, we observed a 5‐HT1A-by-5-HTT and group-by-5-HTT interaction in GABA concentrations, with the 5-HTT high expressing genotype differing between groups and 5‐HT1A genotypes. No significant effects were seen for glutamate or in rACC. To our knowledge, this is the first report of this serotonergic gene-to-gene interaction associated with mood, both among FMS (depression) and across groups (anxiety). Additionally, our findings provide evidence of an association between the serotonergic system and thalamic GABA concentrations, with individuals possessing genetically inferred high serotonergic signalling exhibiting the highest GABA concentrations, possibly enhancing GABAergic inhibitory effects via 5-HT.
Highlights
Within the central nervous system, serotonin (5-hydroxtryptamine, 5-HT) is synthesized in the brainstem raphe nuclei, with serotonergic projections ascending throughout the brain
Anxiety and pain‐relevant characteristics As expected, significant group differences were observed in BDI, HAD, PCS and VASnow, with fibromyalgia subjects (FMS) showing higher current pain, higher levels of anxiety, depression and pain catastrophizing (Table 1)
Regarding thalamic Glutamate and ɣ-aminobutyric acid (GABA) concentrations, a significant effect was found for 5‐HT1A, which was qualified by a 5‐HT1Aby-5‐ HT1A receptors and the serotonin transporter (5-HTT) interaction with higher relative and absolute GABA concentrations in 5‐HT1A CC compared to G-carriers, in the 5-HTT high expressing genotype
Summary
Within the central nervous system, serotonin (5-hydroxtryptamine, 5-HT) is synthesized in the brainstem raphe nuclei, with serotonergic projections ascending throughout the brain. The 5-HT metabolism is critically influenced by the main inhibitory serotonergic 5‐ HT1A receptors and the serotonin transporter (5-HTT). Activation of postsynaptic 5‐HT1A receptors, largely found in corticolimbic areas [3, 4], produces physiological responses determined by the target cell, e.g. antidepressant and antinociceptive effects. 5-HTT regulates serotonergic signalling via 5-HT reuptake from the synaptic cleft into the pre-synaptic neuron, controlling availability and duration of 5-HT effects [5, 6]. Given that serotonergic projections modulate a multitude of behavior, mechanisms influencing 5‐ HT signalling are widely implicated in pain, mood and emotion [7,8,9,10,11]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
