Serotonin-1A receptor polymorphism (rs6295) associated with thermal pain perception.

BACKGROUND: Serotonin (5-HT) is highly involved in pain regulation and serotonin-1A (5-HT1A) receptors are important in determining central 5-HT tone. Accordingly, variation in the 5-HT1A receptor gene (HTR1A) may contribute to inter-individual differences in human pain sensitivity. The minor G-allele of the HTR1A single nucleotide polymorphism (SNP) rs6295 attenuates firing of serotonergic neurons and reduces postsynaptic expression of the receptor. Experiments in rodents suggest that 5-HT1A-agonism modulates pain in opposite directions at mild compared to high noxious intensities. Based upon this and several other similar observations, we hypothesized that G-carriers would exhibit a relative hypoalgesia at mild thermal stimuli but tend towards hyperalgesia at higher noxious intensities. METHODS: Fourty-nine healthy individuals were selectively genotyped for rs6295. Heat- and cold-pain thresholds were assessed along with VAS-ratings of a range of suprathreshold noxious heat intensities (45°C-49°C). Nociceptive-flexion reflex (NFR) thresholds were also assessed. RESULTS: Volunteers did not deviate significantly from Hardy-Weinberg equilibrium. G-carriers were less sensitive to threshold-level thermal pain. This relative hypoalgesia was abolished at suprathreshold noxious intensities where G-carriers instead increased their ratings of heat-pain significantly more than C-homozygotes. No differences with regard to NFR-thresholds emerged. CONCLUSION/SIGNIFICANCE: To the best of our knowledge this is the first study of human pain perception on the basis of variation in HTR1A. The results illustrate the importance of including a range of stimulus intensities in assessments of pain sensitivity. In speculation, we propose that an attenuated serotonergic tone may be related to a 'hypo- to hyperalgesic' response-pattern. The involved mechanisms could be of clinical interest as variation in pain regulation is known to influence the risk of developing pain pathologies. Further investigations are therefore warranted

Data from: The effect of a transient immune activation on subjective health perception in two placebo controlled randomised experiments

Background Patient-reported outcomes predict mortality and play increasingly important roles in care, but factors that modify central measures such as health ratings have been little investigated. Building on designated immune-to-brain pathways, we aimed to determine how a short-term induced inflammation response impacts self-reported health status. Methods Lipopolysaccharide injections were used to provoke acute systemic inflammatory responses in healthy men and women and were compared to placebo in two double-blind randomized experiments. In Experiment 1, 8 individuals (mean 24 years; SD=3.7) received lipopolysaccharide 0.8 ng/kg once and placebo once in a cross-over design, and in Experiment 2, 52 individuals received either lipopolysaccharide 0.6 ng/kg or placebo once in a non-cross-over design (28.6 years; SD=7.1). Main outcomes were perceived health (general and current), sickness behaviour (like fatigue, pain and negative affect), and plasma interleukin (IL)-6, IL-8 and TNF-α, before and after injection. Results Compared to placebo, lipopolysaccharide lead to a deterioration in both self-rated general (Experiment 1, b=1.88 for 0.8 ng/kg) and current health (Experiment 1 b=-3.00; and Experiment 2 b=-1.79) 1.5h after injection (p’s<0.01), effects that remained after 4.5 to 5 hours (p’s<0.05). The effect on current health in Experiment 2 was mediated by increased inflammation and sickness behaviour in response to lipopolysaccharide injection (β=-0.28, p=0.01). Conclusion Health is drastically re-evaluated during inflammatory activation. The findings are consistent with notions that inflammation forms part of health-relevant interoceptive computations of bodily state, and hint at one mechanism as to why subjective health predicts longevity

The effect of a transient immune activation on subjective health perception in two placebo controlled randomised experiments.

BACKGROUND:Patient-reported outcomes predict mortality and play increasingly important roles in care, but factors that modify central measures such as health ratings have been little investigated. Building on designated immune-to-brain pathways, we aimed to determine how a short-term induced inflammation response impacts self-reported health status. METHODS:Lipopolysaccharide injections were used to provoke acute systemic inflammatory responses in healthy men and women and were compared to placebo in two double-blind randomized experiments. In Experiment 1, 8 individuals (mean 24 years; SD = 3.7) received lipopolysaccharide 0.8 ng/kg once and placebo once in a cross-over design, and in Experiment 2, 52 individuals received either lipopolysaccharide 0.6 ng/kg or placebo once (28.6 years; SD = 7.1). Main outcomes were perceived health (general and current), sickness behaviour (like fatigue, pain and negative affect), and plasma interleukin-6, interleukin-8 and tumour necrosis factor-α, before and after injection. RESULTS:Compared to placebo, lipopolysaccharide lead to a deterioration in both self-rated general (Experiment 1, b = 1.88 for 0.8 ng/kg) and current health (Experiment 1 b = -3.00; and Experiment 2 b = -1.79) 1.5h after injection (p's<0.01), effects that remained after 4.5 to 5 hours (p's<0.05). The effect on current health in Experiment 2 was mediated by increased inflammation and sickness behaviour in response to lipopolysaccharide injection (β = -0.28, p = 0.01). CONCLUSION:Health is drastically re-evaluated during inflammatory activation. The findings are consistent with notions that inflammation forms part of health-relevant interoceptive computations of bodily state, and hint at one mechanism as to why subjective health predicts longevity

Effects of sustained sleep restriction on mitogen-stimulated cytokines, chemokines and T helper 1/ T helper 2 balance in humans.

BACKGROUND: Recent studies suggest that acute sleep deprivation disrupts cellular immune responses by shifting T helper (Th) cell activity towards a Th2 cytokine profile. Since little is known about more long-term effects, we investigated how five days of sleep restriction would affect pro-inflammatory, chemotactic, Th1- and Th2 cytokine secretion. METHODS: Nine healthy males participated in an experimental sleep protocol with two baseline sleep-wake cycles (sleep 23.00-07.00 h) followed by 5 days with restricted sleep (03.00-07.00 h). On the second baseline day and on the fifth day with restricted sleep, samples were drawn every third hour for determination of cytokines/chemokines (tumor necrosis factor alpha (TNF-α), interleukin (IL) -1β, IL-2, IL-4 and monocyte chemoattractant protein-1 (MCP-1)) after in vitro stimulation of whole blood samples with the mitogen phytohemagglutinin (PHA). Also leukocyte numbers, mononuclear cells and cortisol were analysed. RESULTS: 5-days of sleep restriction affected PHA-induced immune responses in several ways. There was a general decrease of IL-2 production (p<.05). A shift in Th1/Th2 cytokine balance was also evident, as determined by a decrease in IL2/IL4 ratio. No other main effects of restricted sleep were shown. Two significant interactions showed that restricted sleep resulted in increased TNF-α and MCP-1 in the late evening and early night hours (p's<.05). In addition, all variables varied across the 24 h day. CONCLUSIONS: 5-days of sleep restriction is characterized by a shift towards Th2 activity (i.e. lower 1L-2/IL-4 ratio) which is similar to the effects of acute sleep deprivation and psychological stress. This may have implications for people suffering from conditions characterized by excessive Th2 activity like in allergic disease, such as asthma, for whom restricted sleep could have negative consequences

Maternal bereavement and childhood asthma-analyses in two large samples of Swedish children.

Prenatal factors such as prenatal psychological stress might influence the development of childhood asthma.We assessed the association between maternal bereavement shortly before and during pregnancy, as a proxy for prenatal stress, and the risk of childhood asthma in the offspring, based on two samples of children 1-4 (n = 426,334) and 7-12 (n = 493,813) years assembled from the Swedish Medical Birth Register. Exposure was maternal bereavement of a close relative from one year before pregnancy to child birth. Asthma event was defined by a hospital contact for asthma or at least two dispenses of inhaled corticosteroids or montelukast. In the younger sample we calculated hazards ratios (HRs) of a first-ever asthma event using Cox models and in the older sample odds ratio (ORs) of an asthma attack during 12 months using logistic regression. Compared to unexposed boys, exposed boys seemed to have a weakly higher risk of first-ever asthma event at 1-4 years (HR: 1.09; 95% confidence interval [CI]: 0.98, 1.22) as well as an asthma attack during 12 months at 7-12 years (OR: 1.10; 95% CI: 0.96, 1.24). No association was suggested for girls. Boys exposed during the second trimester had a significantly higher risk of asthma event at 1-4 years (HR: 1.55; 95% CI: 1.19, 2.02) and asthma attack at 7-12 years if the bereavement was an older child (OR: 1.58; 95% CI: 1.11, 2.25). The associations tended to be stronger if the bereavement was due to a traumatic death compared to natural death, but the difference was not statistically significant.Our results showed some evidence for a positive association between prenatal stress and childhood asthma among boys but not girls

Heat-pain thresholds.

<p>Heat-pain thresholds exhibited a trend-level difference [U = 210.5, z = −1.4, p = 0.08] between genotype groups such that G-carriers were less sensitive (had higher thresholds) compared to C-homozygotes.</p