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  • 1.
    Ellerbrock, Isabel
    et al.
    Karolinska Inst, Dept Clin Neurosci, Nobels Väg 9, S-17177 Stockholm, Sweden; Karolinska Univ Hosp, Dept Neuroradiol, Stockholm, Sweden.
    Sandström, Angelica
    Karolinska Inst, Dept Clin Neurosci, Nobels Väg 9, S-17177 Stockholm, Sweden; Karolinska Univ Hosp, Dept Neuroradiol, Stockholm, Sweden.
    Tour, Jeanette
    Karolinska Inst, Dept Clin Neurosci, Nobels Väg 9, S-17177 Stockholm, Sweden; Karolinska Univ Hosp, Dept Neuroradiol, Stockholm, Sweden; Blekinge Hosp, Dept Oncol, Karlskrona, Sweden.
    Fanton, Silvia
    Karolinska Inst, Dept Clin Neurosci, Nobels Väg 9, S-17177 Stockholm, Sweden; Karolinska Univ Hosp, Dept Neuroradiol, Stockholm, Sweden.
    Kadetoff, Diana
    Karolinska Inst, Dept Clin Neurosci, Nobels Väg 9, S-17177 Stockholm, Sweden; Karolinska Univ Hosp, Dept Neuroradiol, Stockholm, Sweden; Löwenströmska Hosp, Stockholm Spine Ctr, Upplands Väsby, Sweden.
    Schalling, Martin
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden; Karolinska Univ Hosp, Ctr Mol Med, Stockholm, Sweden.
    Jensen, Karin B.
    Karolinska Inst, Dept Clin Neurosci, Nobels Väg 9, S-17177 Stockholm, Sweden; Karolinska Univ Hosp, Dept Neuroradiol, Stockholm, Sweden.
    Sitnikov, Rouslan
    Karolinska Univ Hosp, MRI Res Ctr, Stockholm, Sweden.
    Kosek, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. Karolinska Inst, Dept Clin Neurosci, Nobels Väg 9, S-17177 Stockholm, Sweden; Karolinska Univ Hosp, Dept Neuroradiol, Stockholm, Sweden.
    Serotonergic gene-to-gene interaction is associated with mood and GABA concentrations but not with pain-related cerebral processing in fibromyalgia subjects and healthy controls2021In: Molecular Brain, ISSN 1756-6606, Vol. 14, no 1, article id 81Article in journal (Refereed)
    Abstract [en]

    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.

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  • 2.
    Rhodin, Annica
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Gröndbladh, Alfhild
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy.
    Ginya, Harumi
    Precision System Science Japan.
    NIlsson, Kent W
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Rosenblad, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Zhou, Qin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Enlund, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Hallberg, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Division of Biological Research on Drug Dependence.
    Gordh, Torsten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Nyberg, Fred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Combined analysis of circulating β-endorphin with gene polymorphisms in OPRM1, CACNAD2 and ABCB1 reveals correlation with pain, opioid sensitivity and opioid-related side effects2013In: Molecular Brain, ISSN 1756-6606, Vol. 6, p. 8-Article in journal (Refereed)
    Abstract [en]

    Background

    Opioids are associated with wide inter-individual variability in the analgesic response and a narrow therapeutic index. This may be partly explained by the presence of single nucleotide polymorphisms (SNPs) in genes encoding molecular entities involved in opioid metabolism and receptor activation. This paper describes the investigation of SNPs in three genes that have a functional impact on the opioid response: OPRM1, which codes for the μ-opioid receptor; ABCB1 for the ATP-binding cassette B1 transporter enzyme; and the calcium channel complex subunit CACNA2D2. The genotyping was combined with an analysis of plasma levels of the opioid peptide β-endorphin in 80 well-defined patients with chronic low back pain scheduled for spinal fusion surgery, and with differential sensitivity to the opioid analgesic remifentanil. This patient group was compared with 56 healthy controls.

    Results

    The plasma β-endorphin levels were significantly higher in controls than in pain patients.

    A higher incidence of opioid-related side effects and sex differences was found in patients with the minor allele of the ABCB1 gene. Further, a correlation between increased opioid sensitivity and the major CACNA2D2 allele was confirmed. A tendency of a relationship between opioid sensitivity and the minor allele of OPRM1 was also found.

    Conclusions

    Although the sample cohort in this study was limited to 80 patients it appears that it was possible to observe significant correlations between polymorphism in relevant genes and various items related to pain sensitivity and opioid response. Of particular interest is the new finding of a correlation between increased opioid sensitivity and the major CACNA2D2 allele. These observations may open for improved strategies in the clinical treatment of chronic pain with opioids.

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