The serotonin transporter gene polymorphism is associated with the susceptibility and the pain severity in Idiopathic Trigeminal Neuralgia patients

Background

To investigate the possible association between the serotonin transporter gene (5-HTTLPR) and rs 25531 polymorphism and the susceptibility and the pain severity in Trigeminal Neuralgia patients.

Methods

A total of 244 TN patients and 280 age and sex matched healthy volunteer were recruited. 5-HTTLPR and rs 25531 genotyping were performed. All patients received the carbamazepine treatment and the treatment response was evaluated at 6 months.

Results

The genotype distribution of 5-HTTLPR between TN patients and controls were significantly different. The TN Patients had a higher prevalence of short-short genotype than controls. The short-short genotype carriers are also significantly associated with higher pain severity and poorer carbamazepine treatment response compared to the long-long genotype carriers. In contrast, the rs 25531 polymorphism was not associated with the susceptibility to TN, neither with the pain severity and the treat response to carbamazepine.

Conclusion

The 5-HTTLPR polymorphism is associated with the susceptibility to TN and pain severity of TN.     

Contribution of serotonin transporter gene polymorphisms to pediatric migraine

BACKGROUND: The serotonin transporter gene is a promising candidate locus for the genetic susceptibility of migraine. OBJECTIVE: Two functional polymorphisms of the serotonin transporter gene (5-HTTLPR and STin2) were analyzed to assess whether these variants are associated with pediatric migraine. METHODS: Eighty-seven Hungarian pediatric migraine patients and 464 controls were genotyped using polymerase chain reaction. Patients suffering from migraine with (n = 38) or without aura (n = 49) were interviewed regarding the clinical symptoms before or during the attacks. RESULTS: There was no difference between genotype or allele distribution of 5-HTTLPR and STin2 polymorphisms in the entire group of migraineurs and controls. Analysis of subgroups showed an association between STin2 and migraine with aura, as the 12,12 homozygote genotype was overrepresented in this group of patients. Furthermore, similar allele and genotype patterns were found in cases with severe vomiting and abdominal pain. CONCLUSIONS: These results confirm and extend the association between the STin2 polymorphism of 5-HTT gene and migraine with aura using pediatric probands. Our data also suggest a novel endophenotype for pediatric migraine characterized by excessive vomiting and abdominal pain during the attack.     

复发性口腔溃疡5-羟色胺转运体启动子基因多态性研究

目的：探讨5-羟色胺转运体启动子区域（5-HTTLPR）基因多态性和复发性口腔溃疡之间是否存在关联性。方法：运用聚合酶链反应技术（PCR）检测分析T87例复发性口腔溃疡患者和96例健康人群的5-HTTLPR基因多态性。结果：两组5-HTTLPR基因型Short／Short（s／s）差异有显著性（x^2-6．423,P=0．044）,提示s／s基因型携带者比L／L和S／L基因型的携带者患RAV的相对风险显著增高。结论：5-羟色胺转运蛋白启动子区的s／s纯合子基因型可能是RALL的易感基因之一。     

溃疡性结肠炎伴抑郁患者5-羟色胺转运体基因多态性相关研究

目的探讨溃疡性结肠炎伴抑郁患者5-羟色胺转运体启动区基因多态性的变化。方法将15例溃疡性结肠炎伴抑郁患者设为研究组,15例溃疡性结肠炎不伴抑郁患者设为对照组,应用聚合酶链反应技术检测两组5-羟色胺转运体启动区基因多态性的分布频率,并进行对比分析。结果研究组5-羟色胺转运体启动区的s／s基因频率显著高于对照组（P〈0．05）,L／S及L／L基因频率均低于对照组,但两组比较差异无显著性（P〉0．05）。结论5-羟色胺转运体启动区基因的S／S基因型可能是溃疡性结肠炎伴抑郁患者的易感基因之一。     

Emotional modulation of pain and spinal nociception in persons with major depressive disorder (MDD)

Major depressive disorder (MDD) is associated with risk for chronic pain, but the mechanisms contributing to the MDD and pain relationship are unclear. To examine whether disrupted emotional modulation of pain might contribute, this study assessed emotional processing and emotional modulation of pain in healthy controls and unmedicated persons with MDD (14 MDD, 14 controls). Emotionally charged pictures (erotica, neutral, mutilation) were presented in 4 blocks. Two blocks assessed physiological-emotional reactions (pleasure/arousal ratings, corrugator electromyography (EMG), startle modulation, skin conductance) in the absence of pain and 2 blocks assessed emotional modulation of pain and the nociceptive flexion reflex (NFR, a physiological measure of spinal nociception) evoked by suprathreshold electric stimulations. Results indicated pictures generally evoked the intended emotional responses; erotic pictures elicited pleasure, subjective arousal, and smaller startle magnitudes, whereas mutilation pictures elicited displeasure, corrugator EMG activation, and subjective/physiological arousal. However, emotional processing was partially disrupted in MDD, as evidenced by a blunted pleasure response to erotica and a failure to modulate startle according to a valence linear trend. Furthermore, emotional modulation of pain was observed in controls but not MDD, even though there were no group differences in NFR threshold or emotional modulation of NFR. Together, these results suggest supraspinal processes associated with emotion processing and emotional modulation of pain may be disrupted in MDD, but brain to spinal cord processes that modulate spinal nociception are intact. Thus, emotional modulation of pain deficits may be a phenotypic marker for future pain risk in MDD.     

Reward circuitry is perturbed in the absence of the serotonin transporter

The serotonin transporter (SERT) modulates the entire serotonergic system in the brain and influences both the dopaminergic and norepinephrinergic systems. These three systems are intimately involved in normal physiological functioning of the brain and implicated in numerous pathological conditions. Here we use high-resolution magnetic resonance imaging (MRI) and spectroscopy to elucidate the effects of disruption of the serotonin transporter in an animal model system: the SERT knock-out mouse. Employing manganese-enhanced MRI, we injected Mn²⁺ into the prefrontal cortex and obtained 3D MR images at specific time points in cohorts of SERT and normal mice. Statistical analysis of co-registered datasets demonstrated that active circuitry originating in the prefrontal cortex in the SERT knock-out is dramatically altered, with a bias towards more posterior areas (substantia nigra, ventral tegmental area, and Raphé nuclei) directly involved in the reward circuit. Injection site and tracing were confirmed with traditional track tracers by optical microscopy. In contrast, metabolite levels were essentially normal in the SERT knock-out by in vivo magnetic resonance spectroscopy and little or no anatomical differences between SERT knock-out and normal mice were detected by MRI. These findings point to modulation of the limbic cortical–ventral striatopallidal by disruption of SERT function. Thus, molecular disruptions of SERT that produce behavioral changes also alter the functional anatomy of the reward circuitry in which all the monoamine systems are involved.     

Family-based analysis of serotonin transporter gene polymorphisms in migraine with and without aura

Genetic epidemiological twin studies have demonstrated a significant heritability for migraine, with > 60% of liability to migraine either with or without aura coming from additive genetic factors. Because of the essential role of serotonin in the pathophysiology and treatment of migraine, genes of the serotonin system are candidates for involvement in migraine. Consequently, we examined two functional VNTR polymorphisms in the serotonin transporter gene, the 5-HTTLPR and the intron 2 VNTR, in a sample of 212 family trios each with a proband with childhood migraine, 153 with migraine without aura (MoA) and 59 with migraine with aura (MA). For the first time, we used transmission disequilibrium test analysis with the program TDTPHASE to examine the transmission of these two markers and their haplotypes to offspring affected by migraine. We found no significant transmission distortion of any marker, with the common L allele of the 5-HTTLPR transmitted 170 times and not transmitted 178 times, and the S allele 130 vs. 122 times. Likewise, the common 12 allele of the intron 2 VNTR was transmitted 201 times and not transmitted 188 times, and the 10 allele 107 vs. 120 times. The markers were not associated with MoA and MA and none of the haplotypes was associated with overall migraine, MoA or MA. The 5-HTTLPR and the intron 2 VNTRs do not play a major role in susceptibility to migraine.     

5-HTTLPR与抑郁症易感性及抗抑郁疗效的相关性

抑郁症给患者、患者家庭和社会都带来极大负担。现代社会,人们对心理健康要求不断提高,这也是提高生活质量的必要条件,因此对抑郁症的早期识别及治疗也尤为重要。已有研究表明5-HTTLPR与抑郁症有相关性,或为抑郁症易感性和抗抑郁疗效的有效指标之一。本文将对5-HTTLPR与抑郁症易感性及抗抑郁疗效的相关性进行综述。     

Serotonin gene polymorphisms and bipolar I disorder: Focus on the serotonin transporter

The pathogenesis of bipolar disorder may involve, at least in part, aberrations in serotonergic neurotransmission. Hence, serotonergic genes are attractive targets for association studies of bipolar disorder. We have reviewed the literature in this field. It is difficult to synthesize results as only one polymorphism per gene was typically investigated in relatively small samples. Nevertheless, suggestive associations are available for the 5HT2A receptor and the serotonin transporter genes. With the availability of extensive polymorphism data and high throughput genotyping techniques, comprehensive evaluation of these genes using adequately powered samples is warranted. We also report on our investigations of the serotonin transporter, SLC6A4 (17q11.1‐q12). An insertion/deletion polymorphism (5HTTLPR) in the promoter region of this gene has been investigated intensively. However, the results have been inconsistent. We reasoned that other polymorphism/s may contribute to the associations and the inconsistencies may be due to variations in linkage disequilibrium (LD) patterns between samples. Therefore, we conducted LD analyses, as well as association and linkage using 12 polymorphisms, including 5HTTLPR. We evaluated two samples. The first sample consisted of 135 US Caucasian nuclear families having a proband with bipolar I disorder (BDI, DSM IV criteria) and available parents. For case‐control analyses, the patients from these families were compared with cord blood samples from local Caucasian live births (n = 182). Our second, independent sample was recruited through the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP‐BD, 545 cases, 548 controls). No significant associations were detected at the individual polymorphism or haplotype level using the case‐control or family‐based analyses. Our analyses do not support association between SLC6A4 and BDI families. Further studies using sub‐groups of BDI are worthwhile.     

No relationship between the ins del polymorphism of the serotonin transporter promoter and pain perception in fibromyalgia patients and healthy controls

Background: In animals, decades of research have shown that serotonin (5‐HT) is involved in endogenous pain inhibition systems, which are deficient in chronic pain disorders such as fibromyalgia (FM). In humans, there is preliminary evidence showing that 5‐HT is involved in the FM pathophysiology. In the current endophenotyping study, we sought to investigate, for the first time in humans, the relationships between the serotonin transporter promoter region (5‐HTTLPR) polymorphism and experimentally‐induced pain perception/inhibition in healthy controls (HC) and FM patients. Methods: Participants were 58 FM patients and 60 HC, who did not differ in age, sex or menstrual cycle. Thermal stimuli were used to measure pain thresholds. Pain inhibition was elicited using a tonic thermal test (Peltier thermode) administered before and after activation of the diffuse noxious inhibitory controls (DNIC) by means of a cold‐pressor test (CPT). Results: Thermal pain thresholds were higher in HC compared to FM patients. Pain ratings during the CPT were lower in HC, relative to FM patients. Also, DNIC efficacy was stronger in HC compared to FM patients. However, there was no relationship between 5‐HTTLPR and experimentally‐induced pain perception/inhibition. Discussion: Our results further confirm that FM is associated with thermal hyperalgesia and deficient DNIC. However, we found no evidence showing that the 5‐HTTLPR polymorphism influences pain perception and DNIC. Potential reasons for this negative result will be discussed. Further endophenotyping studies of 5‐HT‐related gene polymorphisms are required to ascertain the potential relationships between 5‐HT and human pain perception/inhibition.     

Altered allelic distributions of the serotonin transporter gene in migraine without aura and migraine with aura

Allelic variation of the human serotonin transporter gene (HSERT), a highly plausible candidate gene for susceptibility to migraine, was investigated in 266 individuals with migraine, including 173 having migraine without aura (MO), 94 having migraine with aura (MA), 18 with co-occurrence of MO and MA, plus 133 unaffected controls. The distribution of a polymorphism with different forms of a variable tandem number repeat (VNTR) in intron 2 were compared. The MO group had an over-representation of genotypes with two twelve repeat alleles (STin2.12) and a reduction of genotypes containing one ten repeat (STin2.10) compared to controls. The MA group showed a similar pattern, but also a trend towards an increase in genotypes containing the nine repeat allele of the VNTR (STin2.9). Genotypes containing this allele were found in 6.4% of the MA group compared to 2.3% of controls. The group with co-occurrence of MO and MA had a significantly different pattern of overall allele frequency distribution from controls, reflecting a reduction in genotypes containing the STin2.10 allele and a shift both to STin2.9 carriers and to STin2.12 homozygosity. These results support the view that susceptibility to MO and MA has a genetic component, that these disorders are distinct, and that genetic susceptibility may in some cases be associated with a locus at or near the serotonin transporter gene.     

Adaptability to pain is associated with potency of local pain inhibition,but not conditioned pain modulation: A healthy human study

This study investigated the relationship between pain sensitivity, adaptability, and potency of endogenous pain inhibition, including conditioned pain modulation (CPM) and local pain inhibition. Forty-one healthy volunteers (20 male, 21 female) received conditioning stimulation (CS) over 2 sessions in a random order: tonic heat pain (46°C) on the right leg for 7 minutes and cold pressor pain (1°C to 4°C) on the left hand for 5 minutes. Participants rated the intensity of pain continuously using a 0 to 10 electronic visual analogue scale. The primary outcome measures were pressure pain thresholds (PPT) measured at the heterotopic and homotopic location to the CS sites before, during, and 20 minutes after CS. Two groups of participants, pain adaptive and pain nonadaptive, were identified based on their response to pain in the cold pressor test. Pain-adaptive participants showed a pain reduction between peak pain and pain at end of the test by at least 2 of 10 (n = 16); whereas the pain-nonadaptive participants reported unchanged peak pain during 5-minute CS (n = 25). Heterotopic PPTs during the CS did not differ between the 2 groups. However, increased homotopic PPTs measured 20 minutes after CS correlated with the amount of pain reduction during CS. These results suggest that individual sensitivity and adaptability to pain does not correlate with the potency of CPM. Adaptability to pain is associated with longer-lasting local pain inhibition.     

STin2 VNTR polymorphism in the serotonin transporter gene and migraine: pooled and meta-analyses

Data on the association between the SLC6A4 STin2 VNTR polymorphism and migraine are conflicting. To perform pooled and meta-analyses, we searched for studies published until September 2009 using electronic databases (MEDLINE, EMBASE, Science Citation Index) and reference lists of studies. Assessment for eligibility and extraction of data was performed by two independent investigators. We extracted allele and genotype frequencies for each study. We then calculated study-specific and pooled odds ratios (OR) and 95% confidence intervals (CI) assuming allele and genotype models. We also calculated pooled ORs and 95% CIs based on study-specific effect estimates for the allele model. We included five studies investigating the association between the STin2 VNTR polymorphism and migraine. Results from the allele model suggested a protective effect against migraine for the STin2.9 and STin2.10 alleles compared to the STin2.12 allele among populations of European descent, which however was not significant. Results from the genotype model indicated a significant ~25% reduced risk for migraine among carriers of the 10/12 genotype compared with carriers of the 12/12 genotype among all study populations (OR = 0.76, 95% CI 0.60–0.97) for any migraine, which was more pronounced among populations of European descent (OR = 0.68, 95% CI 0.53–0.87). Results for migraine with and without aura were of similar magnitude, but were not statistically significant. Our results suggest a protective effect of non-STin2.12 alleles compared to STin2.12 alleles, respectively, 10/12 and 10/10 genotypes compared to the 12/12 genotype against migraine among populations of European descent. Associations in non-European populations may differ.     

Increased risk for major depression associated with the short allele of the serotonin transporter promoter region (5-HTTLPR-S) and the CYP2C9*3 allele

In the present study, we aimed to analyze the potential relevance of the polymorphism in the promoter region of the serotonin transporter (SERT or 5-HTT) gene (5-HTTLPR) and the risk of suffering major depression (MDD) in a population of patients previously genotyped for CYP2C9. Seventy white European psychiatric outpatients suffering from MDD and a group of 142 healthy volunteers (HVs) were studied. The frequency of subjects carrying the 5-HTTLPR-S allele was higher (P < 0.05) among MDD than in HV. The odds ratio associated with 5-HTTLPR-S allele was 2.03 for the MDD patients in comparison with the HV group. Previously, we found in this population that the CYP2C9*3 allele frequency was higher among this population of MDD patients than in HV. The frequency of subjects with the combination 5-HTTLPR-S and CYP2C9*3 alleles was higher (P < 0.01, odds ratio 3.47) in MDD than in HV. The present findings provide preliminary evidence about the greater risk of suffering MDD for individuals carrying both 5-HTTLPR-S and CYP2C9*3 alleles.     

Gender role expectations of pain is associated with pain tolerance limit but not with pain threshold

Gender role expectations of pain (GREP) was suggested to predict sex differences in pain perception. Our aim was to explore sex differences in GREP and investigate its relationship with heat-pain threshold (HPT) and heat-pain tolerance limit (HPTL). University students (115 males, 134 females) filled the GREP questionnaire. HPT and HPTL were measured in a sample of 72 students. Additionally, GREP values of the present sample were compared with those of the original, American sample to explore possible cultural effects.Both males and females perceive themselves (and their own sex in general) to be less sensitive to pain and less willing to report of pain than the opposite sex. Males perceived themselves and other men, to endure pain relatively similar to women whereas females perceived themselves and other women as less endurable to pain than men. HPT was similar for the two sexes but males had higher HPTL than females. Within each sex, HPTL correlated mainly with self’s perception of pain sensitivity. The American and Israeli samples differed in that Israeli males and females presented stronger stereotypical views towards same and opposite sexes.Both males and females held stereotypical “macho” attitude towards themselves with regard to pain sensitivity and willingness to report of pain however only females held stereotypical, “macho” attitude towards themselves with regard to pain endurance. The sex differences in GREP and in HPTL and the correlations between GREP items and experimental thresholds suggest that the relationship between GREP and experimental pain is complex and sex-specific. It also appears that GREP is affected by culture.     

Racial/ethnic differences in the experience of chronic pain

The purpose of this study was to examine racial/ethnic-related differences in a four-stage model of the processing of chronic pain. The subjects were 1557 chronic pain patients (White=1084, African American=473) evaluated at a pain management clinic at a large southeastern university medical center. Using an analysis of covariance controlling for pain duration and education, African American patients reported significantly higher levels of pain unpleasantness, emotional response to pain, and pain behavior, but not pain intensity than Whites. Differences were largest for the unpleasantness and emotion measures, particularly depression and fear. The groups differed by approximately 1.0 visual analogue scale unit, a magnitude that may be clinically significant. Racial/ethnic differences in the linear relationship between stages were also tested using structural equation modeling and LISREL-8. The results indicate differences in linear associations between pain measures with African Americans showing a stronger link between emotions and pain behavior than Whites.     

5-羟色胺转运体基因多态性与抑郁障碍的关联研究进展

5-羟色胺转运体在情感性精神障碍的发病中起着重要作用,其与抑郁障碍的关联研究一直是热点话题。5-羟色胺转运体基因被认为是抑郁障碍的首要候选基因。目前有关抑郁障碍的药物基因组学研究多集中在5-羟色胺神经递质相关基因上,但其与抑郁障碍的病因及治疗的关联研究未有一致结论。笔者结合国内外研究进展,围绕5-羟色胺转运体的生物学特性、5-羟色胺转运体基因多态性与抑郁障碍的关系及5-羟色胺转运体基因多态性与选择性五羟色胺再摄取抑制剂抗抑郁疗效三方面作一综述。     

Decreased neck muscle strength is highly associated with pain in cervical dystonia patients treated with botulinum toxin injections

OBJECTIVES: To compare the isometric neck muscle strength of cervical dystonia patients treated with botulinum toxin injections with that of healthy control subjects and to evaluate the association between neck strength, neck pain, and disability in these patients. DESIGN: Clinical cross-sectional study. SETTING: Outpatient rehabilitation and neurology clinics in a Finnish hospital. PARTICIPANTS: Twenty-three patients with cervical dystonia with botulinum toxin-treated neck muscles and 23 healthy control subjects. INTERVENTIONS: Not applicable.Main outcome measures Isometric neck strength was measured by a special neck strength measurement system. Disability was measured by the Neck Disability Index, and pain and symptoms of cervical dystonia by a visual analog scale. RESULTS: Isometric neck strength in all directions measured was significantly lower (25%-44%) in the cervical dystonia patients than in the healthy controls. Neck pain levels reported during the strength tests (r range, -.36 to -.70) and neck pain experienced during the preceding week (r range, -.52 to -.63) were inversely associated with isometric strength results. The difference between sides in rotation strength was 35% in the patient group (P<.001), whereas no significant difference between sides was found in the healthy controls. Fifty-one percent of the patients reported moderate or severe disability. Pain, stiffness, and incorrect position of the head were the most prominent symptoms. CONCLUSIONS: Cervical dystonia patients with botulinum toxin-treated neck muscles showed significantly lower maximal neck strength than healthy controls. The patients also had a statistically significant difference between sides in neck rotation strength. Thus, strength measures may be useful to detect disturbance in the function of the neck muscles.     

Escitalopram is associated with reductions in pain severity and pain interference in opioid dependent patients with depressive symptoms

Pain is common among opioid-dependent patients, yet pharmacologic strategies are limited. The aim of this study was to explore whether escitalopram, a selective serotonin reuptake inhibitor, was associated with reductions in pain. The study used longitudinal data from a randomized, controlled trial that evaluated the effects of escitalopram on treatment retention in patients with depressive symptoms who were initiating buprenorphine/naloxone for treatment of opioid dependence. Participants were randomized to receive escitalopram 10 mg or placebo daily. Changes in pain severity, pain interference, and depression were assessed at 1-, 2-, and 3-month visits with the visual analog scale, Brief Pain Inventory, and the Beck Depression Inventory II, respectively. Fixed-effects estimators for panel regression models were used to assess the effects of intervention on changes in outcomes over time. Additional models were estimated to explore whether the intervention effect was mediated by within-person changes in depression. In this sample of 147 adults, we found that participants randomized to escitalopram had significantly larger reductions on both pain severity (b = −14.34, t = −2.66, P < .01) and pain interference (b = −1.20, t = −2.23, P < .05) between baseline and follow-up. After adjusting for within-subject changes in depression, the estimated effects of escitalopram on pain severity and pain interference were virtually identical to the unadjusted effects. This study of opioid-dependent patients with depressive symptoms found that treatment with escitalopram was associated with clinically meaningful reductions in pain severity and pain interference during the first 3 months of therapy.     

The impact of serotonin transporter (5-HTTLPR) genotype on the development of resting-state functional connectivity in children and adolescents: a preliminary report

A fundamental component of brain development is the formation of large-scale networks across the cortex. One such network, the default network, undergoes a protracted development, displaying weak connectivity in childhood that strengthens in adolescence and becomes most robust in adulthood. Little is known about the genetic contributions to default network connectivity in adulthood or during development. Alterations in connectivity between posterior and frontal portions of the default network have been associated with several psychological disorders, including anxiety, autism spectrum disorders, schizophrenia, depression, and attention-deficit/hyperactivity disorder. These disorders have also been linked to variants of the serotonin transporter linked polymorphic region (5-HTTLPR). The L_A allele of 5-HTTLPR results in higher serotonin transporter expression than the S allele or the rarer L_G allele. 5-HTTLPR may influence default network connectivity, as the superior medial frontal region has been shown to be sensitive to changes in serotonin. Also, serotonin as a growth factor early in development may alter large-scale networks such as the default network. The present study examined the influence of 5-HTTLPR variants on connectivity between the posterior and frontal structures and its development in a cross-sectional study of 39 healthy children and adolescents. We found that children and adolescents homozygous for the S allele (S/S, n = 10) showed weaker connectivity in the superior medial frontal cortex compared to those homozygous for the L_A allele (L_A/L_A, n = 13) or heterozygotes (S/L_A, S/L_G, n = 16). Moreover, there was an age-by-genotype interaction, such that those with L_A/L_A genotype had the steepest age-related increase in connectivity between the posterior hub and superior medial frontal cortex, followed by heterozygotes. In contrast, individuals with the S/S genotype had the least age-related increase in connectivity strength. This preliminary report expands our understanding of the genetic influences on the development of large-scale brain connectivity and lays down the foundation for future research and replication of the results with a larger sample.