Carmen Walter

Meta-analysis of the relevance of the OPRM1 118A>G genetic variant for pain treatment.

ABSTRACT Regard of functional pharmacogenetic polymorphisms may further the success of pain therapy by adopting individualized approaches. The μ‐opioid receptor gene (OPRM1) 118A>G polymorphism is a promising candidate for both opioid effects and pain because of both biological reasonability and apparent experimental and clinical evidence. We analyzed its importance for pain therapy using a meta‐analytic approach to studies relating it to opioid pain therapy. Data from suitable studies selected from hits of a PubMed search for “OPRM1” were independently extracted by two authors. The meta‐analysis included phenotypes by OPRM1 genotype (opioid dosing, pain, and side effects), publication year, diagnostic status, proportion of male study participants, and whether genotype frequencies agreed with Hardy–Weinberg equilibrium. We found no consistent association between OPRM1 118A>G genotypes and most of the phenotypes in a heterogeneous set of eight clinical studies. Only weak evidence of an association with less nausea (effect size, Cohen’s d = −0.21, p = 0.037) and of increased opioid dosage requirements (d = 0.56, p = 0.018) in homozygous carriers of the G allele was obtained. This indicates that despite initially promising results, available evidence of the clinical relevance of the OPRM1 118A>G polymorphism does not withhold a meta‐analysis. This discourages basing personalized therapeutic concepts of pain therapy on OPRM1 118A>G genotyping at the present state of evidence.

Separating brain processing of pain fromthat of stimulus intensity.

Regions of the brain network activated by painful stimuli are also activated by nonpainful and even nonsomatosensory stimuli. We therefore analyzed where the qualitative change from nonpainful to painful perception at the pain thresholds is coded. Noxious stimuli of gaseous carbon dioxide (n = 50) were applied to the nasal mucosa of 24 healthy volunteers at various concentrations from 10% below to 10% above the individual pain threshold. Functional magnetic resonance images showed that these trigeminal stimuli activated brain regions regarded as the “pain matrix.” However, most of these activations, including the posterior insula, the primary and secondary somatosensory cortex, the amygdala, and the middle cingulate cortex, were associated with quantitative changes in stimulus intensity and did not exclusively reflect the qualitative change from nonpainful to pain. After subtracting brain activations associated with quantitative changes in the stimuli, the qualitative change, reflecting pain‐exclusive activations, could be localized mainly in the posterior insular cortex. This shows that cerebral processing of noxious stimuli focuses predominately on the quantitative properties of stimulus intensity in both their sensory and affective dimensions, whereas the integration of this information into the perception of pain is restricted to a small part of the pain matrix. Hum Brain Mapp, 2012.

µ-opioid receptor gene variant OPRM1 118 A>G: a summary of its molecular and clinical consequences for pain

The human µ-opioid receptor variant 118 A>G (rs1799971) has become one of the most analyzed genetic variants in the pain field. At the molecular level, the variant reduces opioid receptor signaling efficiency and expression, the latter probably via a genetic-epigenetic interaction. In experimental settings, the variant was reproducibly associated with decreased effects of exogenous opioids. However, this translates into very small clinical effects (meta-analysis of 14 studies: Cohens d = 0.096; p = 0.008), consisting of slightly higher opioid dosing requirements in peri- and post-operative settings. An effect can neither be maintained for chronic analgesic therapy nor for opioid side effects. It seems unlikely that further studies will reveal larger effect sizes and, therefore, further analyses appear unwarranted. Thus, due to its small effect size, the SNP is without major clinical relevance as a solitary variant, but should be regarded as a part of complex genotypes underlying pain and analgesia.

The Human Operculo-Insular Cortex Is Pain-Preferentially but Not Pain-Exclusively Activated by Trigeminal and Olfactory Stimuli

Increasing evidence about the central nervous representation of pain in the brain suggests that the operculo-insular cortex is a crucial part of the pain matrix. The pain-specificity of a brain region may be tested by administering nociceptive stimuli while controlling for unspecific activations by administering non-nociceptive stimuli. We applied this paradigm to nasal chemosensation, delivering trigeminal or olfactory stimuli, to verify the pain-specificity of the operculo-insular cortex. In detail, brain activations due to intranasal stimulation induced by non-nociceptive olfactory stimuli of hydrogen sulfide (5 ppm) or vanillin (0.8 ppm) were used to mask brain activations due to somatosensory, clearly nociceptive trigeminal stimulations with gaseous carbon dioxide (75% v/v). Functional magnetic resonance (fMRI) images were recorded from 12 healthy volunteers in a 3T head scanner during stimulus administration using an event-related design. We found that significantly more activations following nociceptive than non-nociceptive stimuli were localized bilaterally in two restricted clusters in the brain containing the primary and secondary somatosensory areas and the insular cortices consistent with the operculo-insular cortex. However, these activations completely disappeared when eliminating activations associated with the administration of olfactory stimuli, which were small but measurable. While the present experiments verify that the operculo-insular cortex plays a role in the processing of nociceptive input, they also show that it is not a pain-exclusive brain region and allow, in the experimental context, for the interpretation that the operculo-insular cortex splay a major role in the detection of and responding to salient events, whether or not these events are nociceptive or painful.

Consequences of a human TRPA1 genetic variant on the perception of nociceptive and olfactory stimuli.

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 (13.1±1.5 versus 12.3±1.6 correct discriminations) and indicated a higher intensity of the H2S stimuli (29.2±13.2 versus 21±12.8 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.

Exogenous delta⁹-tetrahydrocannabinol influences circulating endogenous cannabinoids in humans.

Abstract Delta9-tetrahydrocannabinol (THC) competes with the endogenous cannabinoids arachidonoyl ethanolamide (anandamide) and 2-arachidonoyl glycerol (2-AG) at cannabinoid receptors. This may cause adaptive changes in the endocannabinoid signaling cascade with possible consequences for the biological functions of the endocannabinoid system. We show that administration of a single oral dose of 20 mg THC to 30 healthy volunteers resulted in higher circulating concentrations of anandamide, 2-AG, palmitoyl ethanolamide, and oleoylethanolamide at 2 and 3 hours after administration as compared with placebo. At 2 hours after THC administration, changes in oleoylethanolamide plasma concentrations from baseline were linearly related to the THC plasma concentrations. In rats, treatment with the CB1/CB2 agonist WIN 55,212 also increased plasma endocannabinoid concentrations. However, this was associated with a decrease of ethanolamide endocannabinoids in specific brain regions including spinal cord, cortex, and hypothalamus; whereas 2-arachidonoyl glycerol increased in the cortex. Thus, administration of THC to human volunteers influenced the concentrations of circulating endocannabinoids, which was mimicked by WIN-55,212 in rats, suggesting that exogenous cannabinoids may lead to changes in the endocannabinoid system that can be detected in plasma.

Brain Mapping-Based Model of Δ 9 -Tetrahydrocannabinol Effects on Connectivity in the Pain Matrix

Cannabinoids receive increasing interest as analgesic treatments. However, the clinical use of Δ9-tetrahydrocannabinol (Δ9-THC) has progressed with justified caution, which also owes to the incomplete mechanistic understanding of its analgesic effects, in particular its interference with the processing of sensory or affective components of pain. The present placebo-controlled crossover study therefore focused on the effects of 20 mg oral THC on the connectivity between brain areas of the pain matrix following experimental stimulation of trigeminal nocisensors in 15 non-addicted healthy volunteers. A general linear model (GLM) analysis identified reduced activations in the hippocampus and the anterior insula following THC administration. However, assessment of psychophysiological interaction (PPI) revealed that the effects of THC first consisted in a weakening of the interaction between the thalamus and the secondary somatosensory cortex (S2). From there, dynamic causal modeling (DCM) was employed to infer that THC attenuated the connections to the hippocampus and to the anterior insula, suggesting that the reduced activations in these regions are secondary to a reduction of the connectivity from somatosensory regions by THC. These findings may have consequences for the way THC effects are currently interpreted: as cannabinoids are increasingly considered in pain treatment, present results provide relevant information about how THC interferes with the affective component of pain. Specifically, the present experiment suggests that THC does not selectively affect limbic regions, but rather interferes with sensory processing which in turn reduces sensory-limbic connectivity, leading to deactivation of affective regions.

THC may reproducibly induce electrical hyperalgesia in healthy volunteers

An utility of cannabis-based medicines in pain has been persistently in the focus of pain research and is the topic of many scientific reports including the European Journal of Pain where a search for ‘cannabis’ at http://onlinelibrary.wiley.com/journal/ 10.1002/%28ISSN%291532-2149 on 12 June 2014 resulted in 43 hits including publications in the last few years about cannabis effects on pain in humans (Kress and Chapman, 2006; Conte et al., 2009; Sánchez Robles et al., 2012; Serpell et al., 2014). Indeed, cannabinoids are being increasingly considered as an indispensable option in pain treatment, although their introduction into clinical pain therapy is progressing with justifiable caution (Kraft, 2012). This is not only due to the addiction potential of cannabinoids, in particular extracts from Cannabis sativa, but also to the incomplete understanding of the mechanisms of cannabinoid antinociception. This lack of clarity is reflected in the heterogeneous outcomes of human studies on the effects of cannabinoids on pain states (Kraft, 2012). A particularly unexpected and remarkable observation in a human investigation on cannabis analgesia was the induction of hyperalgesia to experimental electrical pain stimuli following administration of a single oral dose of 15 mg Δ-tetrahydrocannabinol (THC) to 18 healthy young (age 23.5 ± 2.6 years) women (Kraft et al., 2008). This suggested that cannabinoids, under certain conditions, may harm rather than cure pain patients, a possibility that may be highly relevant for individualized pain therapy. We report that THC-induced hyperalgesia to experimental electrical pain stimuli at tolerance intensity is a reproducible observation, made in the context of stimulus calibration for a human experimental pain study on cannabis effects on processing of nociceptive information (Walter et al., 2011; Lötsch et al., 2013). Specifically, in a placebo-controlled, two-way, crossover study, 30 healthy volunteers (15 men) aged 27.4 ± 2.8 years and with normal body mass index (20–26.1 kg/cm; Declaration of Helsinki adhered to, including approval by Ethics Committee of the Medical Faculty of the Goethe-University, Frankfurt, Germany, and written informed consent from all participants) had received oral doses of either 20 mg THC (two capsules of 10 mg THC dissolved in Adeps solidus) or placebo (Walter et al., 2011; Lötsch et al., 2013). The pain tolerance thresholds to electrical stimuli (5 Hz sine waves 0–20 mA, raised by 0.2 mA/s and applied via gold electrodes to the middle finger of the right hand; Neurometer® CPT, Neurotron Inc., Baltimore, MD, USA) were determined at baseline and 3 h post placebo/THC application. While the suitability of these technical data to reproduce a potentially important result has been published previously (Kraft

Olfactory drug effects approached from human-derived data

The complexity of the sense of smell makes adverse olfactory effects of drugs highly likely, which can impact a patients quality of life. Here, we present a bioinformatics approach that identifies drugs with potential olfactory effects by connecting drug target expression patterns in human olfactory tissue with drug-related information and the underlying molecular drug targets taken from publically available databases. We identified 71 drugs with listed olfactory effects and 147 different targets. Taking the target-based approach further, we found additional drugs with potential olfactory effects, including 152 different substances interacting with genes expressed in the human olfactory bulb. Our proposed bioinformatics approach provides plausible hypotheses about mechanistic drug effects for drug discovery and repurposing and, thus, would be appropriate for use during drug development.

Extended cortical activations during evaluating successive pain stimuli

Comparing pain is done in daily life and involves short-term memorizing and attention focusing. This event-related functional magnetic resonance imaging study investigated the short-term brain activations associated with the comparison of pain stimuli using a delayed discrimination paradigm. Fourteen healthy young volunteers compared two successive pain stimuli administered at a 10 s interval to the same location at the nasal mucosa. Fourteen age- and sex-matched subjects received similar pain stimuli without performing the comparison task. With the comparison task, the activations associated with the second pain stimulus were significantly greater than with the first stimulus in the anterior insular cortex and the primary somatosensory area. This was observed on the background of a generally increased stimulus-associated brain activation in the presence of the comparison task that included regions of the pain matrix (insular cortex, primary and secondary somatosensory area, midcingulate cortex, supplemental motor area) and regions associated with attention, decision making, working memory and body recognition (frontal and temporal gyri, inferior parietal lobule, precuneus, lingual cortices). This data provides a cerebral correlate for the role of pain as a biological alerting system that gains the subjects attention and then dominates most other perceptions and activities involving pain-specific and non-pain-specific brain regions.