| 1. |
- Jensen, Karin B, et al.
(author)
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Increased sensitivity to thermal pain following a single opiate dose is influenced by the COMT val(158)met polymorphism.
- 2009
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In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 4:6
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Journal article (peer-reviewed)abstract
- Increased pain sensitivity after opioid administration (opioid-induced hyperalgesia) and/or repeated painful stimuli is an individually varying and clinically important phenomenon. The functional polymorphism (val(158)met) of the Catechol-O-methyltransferase (COMT) gene regulates the metabolism of dopamine/noradrenaline. Individuals homozygous for the met(158) allele have been reported to have increased pain sensitivity and there are findings of lower micro-opioid system activation during sustained pain. We hypothesized that met/met individuals would exhibit higher pain sensitization and opioid-induced hyperalgesia in response to repeated pain stimuli and an intravenous injection of an opioid drug. Participants were 43 healthy subjects who went through an experiment where five blocks of pain were induced to the hand using a heat probe. After each stimulus subjects rated the pain on a visual analogue scale (VAS) from 0 mm (no pain) to 100 mm (worst possible pain). Before the second stimulus there was an intravenous injection of a rapid and potent opioid drug. At baseline there was no difference in pain ratings between the COMTval(158)met genotypes, F(2, 39)<1. However, a repeated measures ANOVA for all five stimuli revealed a main effect for COMTval(158)met genotype, F(2, 36) = 4.17, p = 0.024. Met/met individuals reported significantly more pain compared to val/val, p = 0.010. A pairwise comparison of baseline and the opioid intervention demonstrated that analgesia was induced in all groups (p = 0.042) without a separating effect for genotype (n.s). We suggest that the initial response of the descending pain system is not influenced by the COMTval(158)met polymorphism but when the system is challenged the difference is revealed. An important clinical implication of this may be that the COMTval(158)met related differences may be more expressed in individuals where the inhibitory system is already challenged and sensitive, e.g. chronic pain patients. This has to be proven in future studies where the impact of the COMTval(158)met polymorphism on opioid treatment in patients is addressed.
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| 2. |
- Kosek, Eva, et al.
(author)
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Genetic variation in the serotonin transporter gene (5-HTTLPR, rs25531) influences the analgesic response to the short acting opioid Remifentanil in humans.
- 2009
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In: Molecular Pain. - : SAGE Publications. - 1744-8069. ; 5
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Journal article (peer-reviewed)abstract
- BACKGROUND: There is evidence from animal studies that serotonin (5-HT) can influence the antinociceptive effects of opioids at the spinal cord level. Therefore, there could be an influence of genetic polymorphisms in the serotonin system on individual variability in response to opioid treatment of pain. The serotonin transporter (5-HTT) is a key regulator of serotonin metabolism and availability and its gene harbors several known polymorphisms that are known to affect 5-HTT expression (e.g. 5-HTTLPR, rs25531). The aim of this study was to investigate if the triallelic 5-HTTLPR influences pain sensitivity or the analgesic effect of opioids in humans. 43 healthy volunteers (12 men, 31 women, mean age 26 years) underwent heat pain stimulations before and after intravenous injection of Remifentanil; a rapid and potent opioid drug acting on micro-type receptors. Subjects rated their perceived pain on a visual analogue scale (VAS). All participants were genotyped for the 5-HTTLPR and the rs25531 polymorphism. We recruited by advertising, with no history of drug abuse, chronic pain or psychiatric disorders.RESULTS: At baseline, there was no difference in pain ratings for the different triallelic 5-HTTLPR genotype groups. However, the opiod drug had a differential analgesic effect depending on the triallelic 5-HTTLPR genotype. Remifentanil had a significantly better analgesic effect in individuals with a genotype coding for low 5-HTT expression (SA/SA and SA/LG) as compared to those with high expression(LA/LA), p < 0.02. The analgesic effect for the three different genotype groups was linear to degree of 5-HTT expression.CONCLUSION: This is the first report showing an influence of the triallelic 5-HTTLPR on pain sensitivity or the analgesic effect of opioids in humans. Previously the 5-HTTLPR s-allele has been associated with higher risk of developing chronic pain conditions but in this study we show that the genotype coding for low 5-HTT expression is associated with a better analgesic effect of an opioid. The s-allele has been associated with downregulation of 5-HT1 receptors and we suggest that individuals with a desensitization of 5-HT1 receptors have an increased analgesic response to opioids during acute pain stimuli, but may still be at increased risk of developing chronic pain conditions.
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| 3. |
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| 4. |
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| 5. |
- Lindstedt, Fredrik, et al.
(author)
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Conditioned pain modulation is associated with common polymorphisms in the serotonin transporter gene.
- 2011
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In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 6:3
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Journal article (peer-reviewed)abstract
- BACKGROUND: Variation in the serotonin transporter (5-HTT) gene (SLC6A4) has been shown to influence a wide range of affective processes. Low 5-HTT gene-expression has also been suggested to increase the risk of chronic pain. Conditioned pain modulation (CPM)--i.e. 'pain inhibits pain'--is impaired in chronic pain states and, reciprocally, aberrations of CPM may predict the development of chronic pain. Therefore we hypothesized that a common variation in the SLC6A4 is associated with inter-individual variation in CPM. Forty-five healthy subjects recruited on the basis of tri-allelic 5-HTTLPR genotype, with inferred high or low 5-HTT-expression, were included in a double-blind study. A submaximal-effort tourniquet test was used to provide a standardized degree of conditioning ischemic pain. Individualized noxious heat and pressure pain thresholds (PPTs) were used as subjective test-modalities and the nociceptive flexion reflex (NFR) was used to provide an objective neurophysiological window into spinal processing.RESULTS: The low, as compared to the high, 5-HTT-expressing group exhibited significantly reduced CPM-mediated pain inhibition for PPTs (p = 0.02) and heat-pain (p = 0.02). The CPM-mediated inhibition of the NFR, gauged by increases in NFR-threshold, did not differ significantly between groups (p = 0.75). Inhibition of PPTs and heat-pain were correlated (Spearman's rho = 0.35, p = 0.02), whereas the NFR-threshold increase was not significantly correlated with degree of inhibition of these subjectively reported modalities.CONCLUSIONS: Our results demonstrate the involvement of the tri-allelic 5-HTTLPR genotype in explaining clinically relevant inter-individual differences in pain perception and regulation. Our results also illustrate that shifts in NFR-thresholds do not necessarily correlate to the modulation of experienced pain. We discuss various possible mechanisms underlying these findings and suggest a role of regulation of 5-HT receptors along the neuraxis as a function of differential 5-HTT-expression.
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| 6. |
- Lindstedt, Fredrik, et al.
(author)
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Perception of thermal pain and the thermal grill illusion is associated with polymorphisms in the serotonin transporter gene.
- 2011
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In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 6:3
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Journal article (peer-reviewed)abstract
- AIM: The main aim of this study was to assess if the perception of thermal pain thresholds is associated with genetically inferred levels of expression of the 5-HT transporter (5-HTT). Additionally, the perception of the so-called thermal grill illusion (TGI) was assessed. Forty-four healthy individuals (27 females, 17 males) were selected a-priori based on their 5-HTTLPR/rs25531 ('tri-allelic 5-HTTLPR') genotype, with inferred high or low 5-HTT expression. Thresholds for heat- and cold-pain were determined along with the sensory and affective dimensions of the TGI.RESULTS: Thresholds to heat- and cold-pain correlated strongly (rho = -0.58, p<0.001). Individuals in the low 5-HTT-expressing group were significantly less sensitive to heat-pain (p = 0.02) and cold-pain (p = 0.03), compared to the high-expressing group. A significant gender-by-genotype interaction also emerged for cold-pain perception (p = 0.02); low 5-HTT-expressing females were less sensitive. The TGI was rated as significantly more unpleasant (affective-motivational dimension) than painful (sensory-discriminatory dimension), (p<0.001). Females in the low 5-HTT expressing group rated the TGI as significantly less unpleasant than high 5-HTT expressing females (p<0.05), with no such differences among men.CONCLUSION/SIGNIFICANCE: We demonstrate an association between inferred low 5-HTT expression and elevated thresholds to thermal pain in healthy non-depressed individuals. Despite the fact that reduced 5-HTT expression is a risk factor for chronic pain we found it to be related to hypoalgesia for threshold thermal pain. Low 5-HTT expression is, however, also a risk factor for depression where thermal insensitivity is often seen. Our results may thus contribute to a better understanding of the molecular underpinnings of such paradoxical hypoalgesia. The results point to a differential regulation of thermoafferent-information along the neuraxis on the basis of 5-HTT expression and gender. The TGI, suggested to rely on the central integration of thermoafferent-information, may prove a valuable tool in probing the affective-motivational dimension of these putative mechanisms.
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| 8. |
- Lonsdorf, Tina B
(author)
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Genetic gating of human fear, fear learning and extinction : psychophysiological, brain imaging (fMRI) and clinical studies
- 2010
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Doctoral thesis (other academic/artistic)abstract
- Individuals differ in their reaction to the same environmental stressor. After being opposed to the same trauma, some individuals will develop affective pathologies, while others will not. This is assumed to result, at least partly, from a differential genetic vulnerability. Fear conditioning and extinction have been suggested to be mechanisms involved in anxiety disorders and treatment respectively and represent laboratory models to study the reaction of individuals to a stressor in a controlled setting. In this thesis we investigated the effect of common polymorphisms on fear conditioning and extinction (Study I & II) and aimed to translate our results into the clinical setting using a sample of patients suffering from panic disorder (Study III & IV). As the amygdala is the core region involved in fear learning and extinction as well as highly implicated in anxiety disorders, we also studied the effect of common polymorphisms on amygdala reactivity and habituation to negative emotional stimuli using functional magnetic resonance imaging (Study V). In Study I we report facilitated fear conditioning in healthy individuals carrying at least one 5 ] HTTLPR s ]allele (as opposed to non ]carriers, l/l), and resistance to extinction in individuals with the COMTval158met met/met genotype (as opposed to val ]allele carriers), using fearpotentiated startle (FPS) as an index of conditioned fear. Similarly, in Study II we show that also carriers of the BDNFval66met met ]allele (as opposed to non ]carriers, val/val) display deficits in the acquisition of FPS reactions. In Study III and IV we aimed to translate the experimental findings from Study I into a clinical setting using a sample of patients suffering from panic disorder. In Study III, we report a more severe symptomatic profile (both panic and depressive symptoms) in carriers of the 5 ]HTTLPR s ]allele and in Study IV, we report reduced efficacy of exposure ]based cognitive behavioural treatment modules in panic patients with the COMTval158met met/met genotype. Study V investigated amygdala reactivity and habituation during the passive viewing of angry faces in healthy volunteers, selected based on gender, 5 ]HTTLPR/rs25531 and COMTval158met genotype. We report higher right amygdala reactivity and less habituation in 5 ]HTTLPR scarriers as opposed to non ]carriers (l/l) as well as enhanced left amygdala reactivity in individuals with the COMT met/met genotype as opposed to those carrying at least one valallele. In sum, the results of this thesis support a role for 5 ]HTTLPR/rs25531, BDNFval66met and COMTval158met in fear learning and extinction respectively which may have important implications for the risk to develop anxiety disorders (in particular after traumatic events) as well as the efficacy of their treatment. In addition, our results may have unraveled a mechanism underlying gene x environment interactions in anxiety disorders. Our finding of slower amygdala habituation may furthermore represent an underlying mechanism of the enhanced amygdala reactivity commonly found in 5 ]HTTLPR s ]carriers in imaging genetic studies.
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| 9. |
- Lonsdorf, Tina B, et al.
(author)
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The COMTval158met polymorphism is associated with symptom relief during exposure-based cognitive-behavioral treatment in panic disorder
- 2010
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In: BMC Psychiatry. - : BioMed Central. - 1471-244X. ; 10
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Journal article (peer-reviewed)abstract
- Background: Cognitive behavioral therapy (CBT) represents a learning process leading to symptom relief and resulting in long-term changes in behavior. CBT for panic disorder is based on exposure and exposure-based processes can be studied in the laboratory as extinction of experimentally acquired fear responses. We have recently demonstrated that the ability to extinguish learned fear responses is associated with a functional genetic polymorphism (COMTval158met) in the COMT gene and this study was aimed at transferring the experimental results on the COMTval158met polymorphism on extinction into a clinical setting. Methods: We tested a possible effect of the COMTval158met polymorphism on the efficacy of CBT, in particular exposure-based treatment modules, in a sample of 69 panic disorder patients. Results: We present evidence that panic patients with the COMTval158met met/met genotype may profit less from (exposure-based) CBT treatment methods as compared to patients carrying at least one val-allele. No association was found with the 5-HTTLPR/rs25531 genotypes which is presented as additional material. Conclusions: We were thus able to transfer findings on the effect of the COMTval158met polymorphism from an experimental extinction study obtained using healthy subjects to a clinical setting. Furthermore patients carrying a COMT val-allele tend to report more anxiety and more depression symptoms as compared to those with the met/met genotype. Limitations of the study as well as possible clinical implications are discussed.
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| 10. |
- Lonsdorf, Tina B, et al.
(author)
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The symptomatic profile of panic disorder is shaped by the 5-HTTLPR polymorphism
- 2009
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In: Progress in Neuro-psychopharmacology and Biological Psychiatry. - : Elsevier BV. - 0278-5846 .- 1878-4216. ; 33:8, s. 1479-1483
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Research review (peer-reviewed)abstract
- The short allele of a functional polymorphism (5-HTTLPR) in the serotonin transporter (5-HTT) promoter is associated with reduced serotonin transporter expression, lower in vivo 5-HTT binding, higher neuroticism and amygdala reactivity as well as facilitated fear conditioning and is a candidate variant for panic disorder. However, case-control studies have consistently failed to show an association between 5-HTTLPR and panic disorder. As psychiatric disorders are broadly defined phenotypes merging different symptoms to syndromes, they may not be very well suited for genetic association studies. An alternative approach is to measure symptoms along continuous symptom dimensions which may more appropriately reflect their biological underpinnings and may reveal subpopulations within clinical diagnostic groups. We recorded the symptomatic profile in 73 in panic disorder patients using observer-rated instruments (Panic Disorder Severity Scale, PDSS; Montgomery-Asberg Depression Rating Scale, MADRS) and hypothesized more severe symptoms in patients carrying the 5-HTTLPR s-allele. We observed a strong association between bi- and triallelic 5-HTTLPR polymorphisms and the symptomatic profile. Carriers of the 5-HTTLPR s-allele suffered from most severe panic and depressive symptoms. Our data highlight the importance of defining appropriate phenotypes for psychiatric genetic studies and demonstrate that the 5-HTTLPR genotype may be related to the symptomatic profiles rather than to the vulnerability to develop panic disorder.
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