Refine
Year of publication
Document Type
- Article (14)
Language
- English (14)
Has Fulltext
- yes (14)
Is part of the Bibliography
- no (14) (remove)
Keywords
- data science (3)
- pain (2)
- Cannabis (1)
- Clincial pharmacology (1)
- Cold pain (1)
- DNA methylation (1)
- Data science (1)
- Heat pain (1)
- Human (1)
- Human experimental pain models (1)
Institute
Purpose: The antifungal drugs ketoconazole and itraconazole reduce serum concentrations of 4β-hydroxycholesterol, which is a validated marker for hepatic cytochrome P450 (CYP) 3A4 activity. We tested the effect of another antifungal triazole agent, fluconazole, on serum concentrations of different sterols and oxysterols within the cholesterol metabolism to see if this inhibitory reaction is a general side effect of azole antifungal agents.
Methods: In a prospective, double-blind, placebo-controlled, two-way crossover design, we studied 17 healthy subjects (nine men, eight women) who received 400 mg fluconazole or placebo daily for 8 days. On day 1 before treatment and on day 8 after the last dose, fasting blood samples were collected. Serum cholesterol precursors and oxysterols were measured by gas chromatography-mass spectrometry-selected ion monitoring and expressed as the ratio to cholesterol (R_sterol).
Results: Under fluconazole treatment, serum R_lanosterol and R_24,25-dihydrolanosterol increased significantly without affecting serum cholesterol or metabolic downstream markers of hepatic cholesterol synthesis. Serum R_4β-, R_24S-, and R_27-hydroxycholesterol increased significantly.
Conclusion: Fluconazole inhibits the 14α-demethylation of lanosterol and 24,25-dihydrolanosterol, regulated by CYP51A1, without reduction of total cholesterol synthesis. The increased serum level of R_4β-hydroxycholesterol under fluconazole treatment is in contrast to the reductions observed under ketoconazole and itraconazole treatments. The question, whether this increase is caused by induction of CYP3A4 or by inhibition of the catabolism of 4β-hydroxycholesterol, must be answered by mechanistic in vitro and in vivo studies comparing effects of various azole antifungal agents on hepatic CYP3A4 activity.
Consequences of a human TRPA1 genetic variant on the perception of nociceptive and olfactory stimuli
(2014)
Background: TRPA1 ion channels are involved in nociception and are also excited by pungent odorous substances. Based on reported associations of TRPA1 genetics with increased sensitivity to thermal pain stimuli, we therefore hypothesized that this association also exists for increased olfactory sensitivity.
Methods: Olfactory function and nociception was compared between carriers (n = 38) and non-carriers (n = 43) of TRPA1 variant rs11988795 G.A, a variant known to enhance cold pain perception. Olfactory function was quantified by assessing the odor threshold, odor discrimination and odor identification, and by applying 200-ms pulses of H2S intranasal. Nociception was assessed by measuring pain thresholds to experimental nociceptive stimuli (blunt pressure, electrical stimuli, cold and heat stimuli, and 200-ms intranasal pulses of CO2).
Results: Among the 11 subjects with moderate hyposmia, carriers of the minor A allele (n = 2) were underrepresented (34 carriers among the 70 normosmic subjects; p = 0.049). Moreover, carriers of the A allele discriminated odors significantly better than non-carriers (13.161.5 versus 12.361.6 correct discriminations) and indicated a higher intensity of the H2S stimuli (29.2613.2 versus 21612.8 mm VAS, p = 0.006), which, however, could not be excluded to have involved a trigeminal component during stimulation. Finally, the increased sensitivity to thermal pain could be reproduced.
Conclusions: The findings are in line with a previous association of a human TRPA1 variant with nociceptive parameters and extend the association to the perception of odorants. However, this addresses mainly those stimulants that involve a trigeminal component whereas a pure olfactory effect may remain disputable. Nevertheless, findings suggest that future TRPA1 modulating drugs may modify the perception of odorants.
Background and Aims: Mutations reducing the function of Nav1.7 sodium channels entail diminished pain perception and olfactory acuity, suggesting a link between nociception and olfaction at ion channel level. We hypothesized that if such link exists, it should work in both directions and gain-of-function Nav1.7 mutations known to be associated with increased pain perception should also increase olfactory acuity.
Methods: SCN9A variants were assessed known to enhance pain perception and found more frequently in the average population. Specifically, carriers of SCN9A variants rs41268673C>A (P610T; n = 14) or rs6746030C>T (R1150W; n = 21) were compared with non-carriers (n = 40). Olfactory function was quantified by assessing odor threshold, odor discrimination and odor identification using an established olfactory test. Nociception was assessed by measuring pain thresholds to experimental nociceptive stimuli (punctate and blunt mechanical pressure, heat and electrical stimuli).
Results: The number of carried alleles of the non-mutated SCN9A haplotype rs41268673C/rs6746030C was significantly associated with the comparatively highest olfactory threshold (0 alleles: threshold at phenylethylethanol dilution step 12 of 16 (n = 1), 1 allele: 10.6±2.6 (n = 34), 2 alleles: 9.5±2.1 (n = 40)). The same SCN9A haplotype determined the pain threshold to blunt pressure stimuli (0 alleles: 21.1 N/m2, 1 allele: 29.8±10.4 N/m2, 2 alleles: 33.5±10.2 N/m2).
Conclusions: The findings established a working link between nociception and olfaction via Nav1.7 in the gain-of-function direction. Hence, together with the known reduced olfaction and pain in loss-of-function mutations, a bidirectional genetic functional association between nociception and olfaction exists at Nav1.7 level.
Genetic association studies have shown their usefulness in assessing the role of ion channels in human thermal pain perception. We used machine learning to construct a complex phenotype from pain thresholds to thermal stimuli and associate it with the genetic information derived from the next-generation sequencing (NGS) of 15 ion channel genes which are involved in thermal perception, including ASIC1, ASIC2, ASIC3, ASIC4, TRPA1, TRPC1, TRPM2, TRPM3, TRPM4, TRPM5, TRPM8, TRPV1, TRPV2, TRPV3, and TRPV4. Phenotypic information was complete in 82 subjects and NGS genotypes were available in 67 subjects. A network of artificial neurons, implemented as emergent self-organizing maps, discovered two clusters characterized by high or low pain thresholds for heat and cold pain. A total of 1071 variants were discovered in the 15 ion channel genes. After feature selection, 80 genetic variants were retained for an association analysis based on machine learning. The measured performance of machine learning-mediated phenotype assignment based on this genetic information resulted in an area under the receiver operating characteristic curve of 77.2%, justifying a phenotype classification based on the genetic information. A further item categorization finally resulted in 38 genetic variants that contributed most to the phenotype assignment. Most of them (10) belonged to the TRPV3 gene, followed by TRPM3 (6). Therefore, the analysis successfully identified the particular importance of TRPV3 and TRPM3 for an average pain phenotype defined by the sensitivity to moderate thermal stimuli.
Aim: Exposure to opioids has been associated with epigenetic effects. Studies in rodents suggested a role of varying degrees of DNA methylation in the differential regulation of μ-opioid receptor expression across the brain.
Methods: In a translational investigation, using tissue acquired postmortem from 21 brain regions of former opiate addicts, representing a human cohort with chronic opioid exposure, μ-opioid receptor expression was analyzed at the level of DNA methylation, mRNA and protein.
Results & conclusion: While high or low μ-opioid receptor expression significantly correlated with local OPRM1 mRNA levels, there was no corresponding association with OPRM1 methylation status. Additional experiments in human cell lines showed that changes in DNA methylation associated with changes in μ-opioid expression were an order of magnitude greater than differences in brain. Hence, different degrees of DNA methylation associated with chronic opioid exposure are unlikely to exert a major role in the region-specificity of μ-opioid receptor expression in the human brain.
Inverted perceptual judgment of nociceptive stimuli at threshold level following inconsistent cues
(2015)
Objective: The perception of pain is susceptible to modulation by psychological and contextual factors. It has been shown that subjects judge noxious stimuli as more painful in a respective suggestive context, which disappears when the modifying context is resolved. However, a context in which subjects judge the painfulness of a nociceptive stimulus in exactly the opposite direction to that of the cues has never been shown so far.
Methods: Nociceptive stimuli (300 ms intranasal gaseous CO2) at the individual pain threshold level were applied after a visual cue announcing the stimulus as either "no pain", merely a "stimulus", or "pain". Among the stimuli at threshold level, other CO2 stimuli that were clearly below or above pain threshold were randomly interspersed. These were announced beforehand in 12 subjects randomly with correct or incorrect cues, i.e., clearly painful or clearly non-painful stimuli were announced equally often as not painful or painful. By contrast, in a subsequent group of another 12 subjects, the stimuli were always announced correctly with respect to the evoked pain.
Results: The random and often incorrect announcement of stimuli clearly below or above pain threshold caused the subjects to rate the stimuli at pain-threshold level in the opposite direction of the cue, i.e., when the stimuli were announced as "pain" significantly more often than as non-painful and vice versa (p < 10-4). By contrast, in the absence of incongruence between announcement and perception of the far-from-threshold stimuli, stimuli at pain threshold were rated in the cued direction.
Conclusions: The present study revealed the induction of associations incongruent with a given message in the perception of pain. We created a context of unreliable cues whereby subjects perceived the stimulus opposite to that suggested by a prior cue, i.e., potentially nociceptive stimuli at pain threshold level that were announced as painful were judged as non-painful and vice versa. These findings are consistent with reported data on the effects of distrust on non-painful cognitive responses.
The comprehensive assessment of pain-related human phenotypes requires combinations of nociceptive measures that produce complex high-dimensional data, posing challenges to bioinformatic analysis. In this study, we assessed established experimental models of heat hyperalgesia of the skin, consisting of local ultraviolet-B (UV-B) irradiation or capsaicin application, in 82 healthy subjects using a variety of noxious stimuli. We extended the original heat stimulation by applying cold and mechanical stimuli and assessing the hypersensitization effects with a clinically established quantitative sensory testing (QST) battery (German Research Network on Neuropathic Pain). This study provided a 246 × 10-sized data matrix (82 subjects assessed at baseline, following UV-B application, and following capsaicin application) with respect to 10 QST parameters, which we analyzed using machine-learning techniques. We observed statistically significant effects of the hypersensitization treatments in 9 different QST parameters. Supervised machine-learned analysis implemented as random forests followed by ABC analysis pointed to heat pain thresholds as the most relevantly affected QST parameter. However, decision tree analysis indicated that UV-B additionally modulated sensitivity to cold. Unsupervised machine-learning techniques, implemented as emergent self-organizing maps, hinted at subgroups responding to topical application of capsaicin. The distinction among subgroups was based on sensitivity to pressure pain, which could be attributed to sex differences, with women being more sensitive than men. Thus, while UV-B and capsaicin share a major component of heat pain sensitization, they differ in their effects on QST parameter patterns in healthy subjects, suggesting a lack of redundancy between these models.
Persistent and, in particular, neuropathic pain is a major healthcare problem with still insufficient pharmacological treatment options. This triggered research activities aimed at finding analgesics with a novel mechanism of action. Results of these efforts will need to pass through the phases of drug development, in which experimental human pain models are established components e.g. implemented as chemical hyperalgesia induced by capsaicin. We aimed at ranking the various readouts of a human capsaicin–based pain model with respect to the most relevant information about the effects of a potential reference analgesic. In a placebo‐controlled, randomized cross‐over study, seven different pain‐related readouts were acquired in 16 healthy individuals before and after oral administration of 300 mg pregabalin. The sizes of the effect on pain induced by intradermal injection of capsaicin were quantified by calculating Cohen's d. While in four of the seven pain‐related parameters, pregabalin provided a small effect judged by values of Cohen's d exceeding 0.2, an item categorization technique implemented as computed ABC analysis identified the pain intensities in the area of secondary hyperalgesia and of allodynia as the most suitable parameters to quantify the analgesic effects of pregabalin. Results of this study provide further support for the ability of the intradermal capsaicin pain model to show analgesic effects of pregabalin. Results can serve as a basis for the designs of studies where the inclusion of this particular pain model and pregabalin is planned.
Background: It is assumed that different pain phenotypes are based on varying molecular pathomechanisms. Distinct ion channels seem to be associated with the perception of cold pain, in particular TRPM8 and TRPA1 have been highlighted previously. The present study analyzed the distribution of cold pain thresholds with focus at describing the multimodality based on the hypothesis that it reflects a contribution of distinct ion channels.
Methods: Cold pain thresholds (CPT) were available from 329 healthy volunteers (aged 18 - 37 years; 159 men) enrolled in previous studies. The distribution of the pooled and log-transformed threshold data was described using a kernel density estimation (Pareto Density Estimation (PDE)) and subsequently, the log data was modeled as a mixture of Gaussian distributions using the expectation maximization (EM) algorithm to optimize the fit.
Results: CPTs were clearly multi-modally distributed. Fitting a Gaussian Mixture Model (GMM) to the log-transformed threshold data revealed that the best fit is obtained when applying a three-model distribution pattern. The modes of the identified three Gaussian distributions, retransformed from the log domain to the mean stimulation temperatures at which the subjects had indicated pain thresholds, were obtained at 23.7 °C, 13.2 °C and 1.5 °C for Gaussian #1, #2 and #3, respectively.
Conclusions: The localization of the first and second Gaussians was interpreted as reflecting the contribution of two different cold sensors. From the calculated localization of the modes of the first two Gaussians, the hypothesis of an involvement of TRPM8, sensing temperatures from 25 - 24 °C, and TRPA1, sensing cold from 17 °C can be derived. In that case, subjects belonging to either Gaussian would possess a dominance of the one or the other receptor at the skin area where the cold stimuli had been applied. The findings therefore support a suitability of complex analytical approaches to detect mechanistically determined patterns from pain phenotype data.
Background: A delta and C fibers are the major pain-conducting nerve fibers, activate only partly the same brain areas, and are differently involved in pain syndromes. Whether a stimulus excites predominantly A delta or C fibers is a commonly asked question in basic pain research but a quick test was lacking so far. Methodology/Principal Findings: Of 77 verbal descriptors of pain sensations, "pricking", "dull" and "pressing" distinguished best (95% cases correctly) between A delta fiber mediated (punctate pressure produced by means of von Frey hairs) and C fiber mediated (blunt pressure) pain, applied to healthy volunteers in experiment 1. The sensation was assigned to A delta fibers when "pricking" but neither "dull" nor "pressing" were chosen, and to C fibers when the sum of the selections of "dull" or "pressing" was greater than that of the selection of "pricking". In experiment 2, with an independent cohort, the three-descriptor questionnaire achieved sensitivity and specificity above 0.95 for distinguishing fiber preferential non-mechanical induced pain (laser heat, exciting A delta fibers, and 5-Hz electric stimulation, exciting C fibers). Conclusion: A three-item verbal rating test using the words "pricking", "dull", and "pressing" may provide sufficient information to characterize a pain sensation evoked by a physical stimulus as transmitted via A delta or via C fibers. It meets the criteria of a screening test by being easy to administer, taking little time, being comfortable in handling, and inexpensive while providing high specificity for relevant information.