Thermal Pain Responses Research Articles

Neurotensin-expressing lateral hypothalamic neurons alleviate neuropathic and inflammatory pain via neurotensin receptor signaling

Persistent, severe pain negatively impacts health and wellbeing, but half of patients do not receive adequate relief from current treatments. Understanding signals that modulate central pain processing could point to new strategies to manage severe pain. Administering Neurotensin (Nts) or Nts receptor (NtsR) agonists into the brain provides analgesia comparable to pharmacologic opioids. However, the endogenous sources of Nts that modify pain processing and might be leveraged for pain relief remained unknown. We previously characterized a large population of Nts-expressing neurons in the lateral hypothalamic area (LHANts neurons) that project to brain regions that participate in descending control of pain processing. We hypothesized that LHANts neurons are an endogenous source of Nts and activating them would alleviate pain dependent on Nts signaling via NtsRs. To test this, we injected NtsCre mice in the LHA with AAVs to cre-dependently express either mCherry (Control) or the excitatory hM3Dq in LHANts neurons, permitting their stimulation after treatment with the hM3Dq ligand clozapine N-oxide (CNO). Activating LHANts neurons had no effect on thermal pain and mechanical responses in naïve mice. By contrast, both spared nerve injury- (SNI) and complete Freund’s adjuvant (CFA)-induced mechanical hypersensitivity was completely reversed by CNO-stimulation of LHANts neurons. Pretreatment with the Nts receptor antagonist SR142948 reduced CNO-mediated analgesia, indicating that LHANts neurons alleviate chronic pain in an Nts receptor-dependent manner. Taken together these data identify LHANts neurons as an endogenous source of Nts that modulates central pain processing and may inform future development of Nts-based targets to treat severe pain.

The P2X7 Hypothesis of Central Post-Stroke Pain.

The present study examined how P2X7 receptor knockout (KO) modulates central post-stroke pain (CPSP) induced by lesions of the ventrobasal complex (VBC) of the thalamus in behaviors, molecular levels, and electrical recording tests. Following the experimental procedure, the wild-type and P2X7 receptor KO mice were injected with 10 mU/0.2 μL type IV collagenase in the VBC of the thalamus to induce an animal model of stroke-like thalamic hemorrhage. Behavioral data showed that the CPSP group induced thermal and mechanical pain. The P2X7 receptor KO group showed reduced thermal and mechanical pain responses compared to the CPSP group. Molecular assessments revealed that the CPSP group had lower expression of NeuN and KCC2 and higher expression of GFAP, IBA1, and BDNF. The P2X7 KO group showed lower expression of GFAP, IBA1, and BDNF but nonsignificant differences in KCC2 expression than the CPSP group. The expression of NKCC1, GABAa receptor, and TrkB did not differ significantly between the control, CPSP, and P2X7 receptor KO groups. Muscimol, a GABAa agonist, application increased multiunit numbers for monitoring many neurons and [Cl-] outflux in the cytosol in the CPSP group, while P2X7 receptor KO reduced multiunit activity and increased [Cl-] influx compared to the CPSP group. P2X4 receptor expression was significantly decreased in the 100 kDa but not the 50 kDa site in the P2X7 receptor KO group. Altogether, the P2X7 hypothesis of CPSP was proposed, wherein P2X7 receptor KO altered the CPSP pain responses, numbers of astrocytes and microglia, CSD amplitude of the anterior cingulate cortex and the medial dorsal thalamus, BDNF expression, [Cl-] influx, and P2X4 expression in 100 kDa with P2X7 receptors. The present findings have implications for the clinical treatment of CPSP symptoms.

Interhemispheric and Corticothalamic White-Matter Dysfunction Underlies Affective Morbidity and Impaired Pain Modulation in Chronic Pain.

Although patients with chronic pain show behavioral signs of impaired endogenous pain modulation, responsible cerebral networks have yet to be anatomically delineated. We used diffusion tensor imaging (DTI) to examine the white-matter alterations in patients with chronic pain compared with healthy subjects. We further measured thermal pain modulatory responses using the offset analgesia (OA) paradigm. We tested whether the white-matter indices be associated with psychophysical parameters reflecting morbidity and modulatory responses of pain in patients, and whether they could serve as diagnostic biomarkers of chronic pain. Twenty-six patients with chronic pain and 18 age- and gender-matched healthy controls were enrolled. After completing psychophysical questionnaires, they underwent OA measurement and whole-brain DTI in a 3 Tesla magnetic resonance imaging scanner. Fractional anisotropy (FA) and radial diffusivity (RD) of the white-matter were computed and compared between the groups with tract-based spatial statistics using the FMRIB Software Library (FSL) software. Correlations were sought among white-matter indices, thermal pain responses, and psychophysical parameters. The white-matter indices and OA-related parameters were tested whether they distinguish patients from controls by receiver operating characteristic analysis. During OA, patients showed a shorter latency to the maximum (maximum visual analog scale [VAS] latency, 16.0 ± 3.7 vs 18.9 ± 3.1 second [mean ± standard deviation, SD]; P = .032) but a longer latency to the minimum pain (OA latency, 15.6 ± 3.5 vs 11.1 ± 4.2 seconds; P = .004) than controls. They showed a smaller mean FA (0.44 ± 0.12 vs 0.45 ± 0.11; P = .012) and a larger mean RD of the global white-matter (0.00057 ± 0.00002 vs 0.00056 ± 0.00002; P = .038) than controls, at specific areas including the corpus callosum, anterior thalamic radiation, and forceps major. FA of the splenium of the corpus callosum was associated with maximum VAS latency (r = 0.493) and OA latency (r = -0.552). The Pain Catastrophizing Scale scores showed strong negative correlations with FA across those specific areas (r = -0.405). Those latencies during OA and white-matter metrics distinguished patients from controls (P < .05). Patients with chronic pain showed dysfunction of the white matter concerned with interhemispheric communication of sensorimotor information as well as descending corticothalamic modulation of pain in association with affective morbidity and altered temporal dynamics of pain perception. We suggest that an impaired interhemispheric modulation of pain, through the corpus callosum, might be a novel cerebral mechanism in chronification of pain.

In vivo evaluation of nephrotoxicity and neurotoxicity of colistin formulated with sodium deoxycholate sulfate in a mice model.

Neurotoxicity and nephrotoxicity are the major dose-limiting factors for the clinical use of colistin against multidrug-resistant (MDR) Gram-negative bacteria. This study aimed to investigate the neurotoxic and nephrotoxic effects of colistin formulated with in-house synthesized sodium deoxycholate sulfate (SDCS) in a mouse model. Male mice C57BL/6 were randomly divided into four groups: control (saline solution), colistin (15mg/kg/day), colistin:SDCS 1:1, and colistin:SDCS 1:2. In the colistin:SDCS treatment groups, the dosage was 15mg/kg/day colistin equivalent; all mice were treated for 7 successive days. The thermal tolerance, body weight gain and organ weights were measured. The levels of serum blood urea nitrogen (BUN), creatinine (Cr), superoxide dismutase (SOD), and catalase (CAT) were assessed. Histopathological damages were assessed on mice organ. The colistin:SDCS formulations significantly improved thermal pain response of the mice comparable to the control group. The administration did not impair kidney function as evidence from BUN and Cr results; however, the oxidative stress biomarkers decreased in the colistin and colistin-SDCS treated mice. Several abnormalities were observed in the kidney, liver, spleen, and sciatic nerve tissues following colistin treatment, which indicated evidence of toxicity. The colistin-SDCS formulations were associated with less acute toxicity and fewer nephrotoxic and neurotoxic changes compared with the colistin alone group which indicated that SDCS attenuated colistin nephrotoxicity and neurotoxicity. This study highlights the potential application of colistin formulated with SDCS for safer clinical use against MDR Gram-negative bacteria.

Neurotensin expressing lateral hypothalamic neurons alleviate neuropathic and inflammatory pain via Nts signaling

The plague of chronic pain has fueled the U.S. opioid epidemic, creating a critical need for novel pain therapeutics that do not cause dependence. In preclinical models, central treatment with the neuropeptide Neurotensin (Nts) or Nts receptor agonists promotes analgesia, suggesting that augmenting Nts system signaling may be useful to treat pain. However, the lack of clarity of the endogenous Nts mechanisms regulating pain has hindered understanding of how to leverage the Nts system for pain relief. The objective of this study was to determine whether the large population of lateral hypothalamic area (LHA) neurons expressing Nts (referred to as LHA Nts neurons) contribute to analgesia. We hypothesized that activating LHA Nts neurons can alleviate chronic pain in an Nts-dependent manner. To test this, we injected Nts Cre mice in the LHA with AAVs to cre-dependently express either mCherry (Control) or excitatory Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) in LHA Nts neurons, permitting their activation after treatment with the DREADD ligand clozapine N-oxide (CNO, 0.3 mg/kg, i.p.). We then measured how DREADD-activation of LHA Nts neurons impacts acute thermal pain (using the hot plate test), spared nerve injury (SNI) pain or complete Freund’s adjuvant (CFA)-induced inflammatory pain measured using the von Frey test. Activating LHA Nts neurons had no effect on thermal pain responses in naïve mice. By contrast, SNI-induced pain hypersensitivity (indicated by reduced paw withdrawal threshold at 7- and 28-days post-injury) was completely reversed by CNO-mediated activation of LHA Nts neurons compared to VEH control. In CFA-treated mice (a model of inflammatory pain), CNO-activating LHA Nts neurons also relieved pain hypersensitivity, increasing paw withdrawal threshold by 30 mins post treatment that gradually reduced to baseline in 5 hours. However, pretreatment with the brain permeable Nts receptor pan-antagonist SR142948 (1mg/kg, i.p, 30 min before VEH/CNO) blocked CNO-mediated analgesia, indicating that LHA Nts neurons alleviate chronic pain in an Nts-dependent manner. Intriguingly, RNAscope analysis revealed that Nts mRNA expression was increased in the LHA in response to CFA and SNI, suggesting that prolonged pain may increase endogenous Nts, with potential to provide analgesia. Taken together these data suggest that activation of LHA Nts neurons alleviates neuropathic and inflammatory pain via Nts signaling, and augmenting Nts signaling via these neurons could hold promise for treating pain. This research was supported by an award from the National Institute of Neurological Disorders under an award to Geoffroy Laumet (R01-NS121259) and an award from the National Institute of Diabetes and Digestive and Kidney Diseases to Gina Leinninger (R01-DK103808). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Age Differences in Thermal Pain Responses: A Direct Laboratory Comparison.

According to a widely cited assertion, older adults are less likely than younger individuals to express pain complaints. Age-related differences in pain responses have been discussed in the literature despite a paucity of research involving direct comparisons of younger and older adults' pain reactions (i.e., verbal, nonverbal) in the context of a single experimental investigation. Our goal was to test the hypothesis that older adults are more stoic than younger adults in their expression of pain. We measured trait stoicism as well as multiple responses to thermal pain. In contrast to suggestions in the literature, equivalence testing indicated that older and younger adults displayed similar verbal and nonverbal pain responses. Our results suggest that older adults are no more stoic about their pain than are younger persons. This is the first attempt to explore a wide array of age differences in pain expression within the context of a single experimental study.

Discovery of Quinoline-Derived Trifluoromethyl Alcohols as Antiepileptic and Analgesic Agents That Block Sodium Channels.

The discovery of novel analgesic agents with high potency, low toxicity and low addictive properties remain a priority. This study aims to identify the analgesic potential of quinoline derived α-trifluoromethylated alcohols (QTA) and their mechanism of action. We synthesized and characterized several compounds of QTAs and screened them for antiepileptic and analgesic activity using zebrafish larvae in high thorough-put behavior analyses system. Toxicity and behavioral screening of 9 compounds (C1-C9) identified four candidates (C2, C3, C7 and C9) with antiepileptic properties that induces specific and reversible reduction in photomotor activity. Importantly, compounds C2 and C3 relieved the thermal pain response in zebrafish larvae indicating analgesic property. Further, using novel in vivo CoroNa green assay, we show that compounds C2 and C3 block sodium channels and reduce inflammatory sodium signals released by peripheral nerve and tissue damage. Thus, we have identified novel QTA compounds with antiepileptic and analgesic properties which could alleviate neuropathic pain.

A231 THE MICROBIOTA-NOCICEPTORS-MICROGLIA AXIS CONTROLS THE DEVELOPMENT AND MAINTENANCE OF CHRONIC VISCERAL HYPERSENSITIVITY

Abstract Background Pain is the most common cause of disability in inflammatory bowel disease (IBD). Current medical interventions control the debilitating clinical symptoms by reducing gastrointestinal (GI) inflammation. Despite successful treatment of active disease, abdominal pain persists during remission, suggesting a high level of plasticity in pain-sensing circuits (hyperalgesic priming) caused by inflammation. What drives this remodelling has remained elusive. We have identified microglia as active players of hyperalgesic priming in IBD. Furthermore, it was recently shown that commensal bacteria control the maturation of microglia in the CNS, suggesting that dysbiosis could influence visceral sensitivity through regulating colonic nociceptors-microglia interaction. Here we test the hypothesis that microbiome-nociceptors-microglia interactions control visceral sensitivity and pain in IBD. Aims We investigated the role of the microbiota in the developmental regulation of colonic nociceptors that express the pain receptor TRPV1. We will identify the microbial factors that control neuron-microglia interactions during bacterial colonization and post-inflammatory dysbiosis. Methods We have developed a germ-free TRPV1-GFP reporter mouse to be used for a combination of behavioural tests and phenotypic characterization of TRPV1+ nociceptors. RNA-sequencing of FACS isolated TRPV1+ neurons of germ-free mice will be used to identify genes that are under the control of the microbiota. We will restore discrepancies observed in germ-free mice by recolonization to assess the impact of the microbiota. Furthermore, we will investigate the regulation of Ahr in TRPV1+ neurons by the microbiota and the effect of its ligands on microglial activation and post-inflammatory visceral pain. Results Measuring somatic pain sensation in naive germ-free and SPF mice, we showed a 15% reduction in thermal pain threshold, as measured by the Hargreaves test, and a 50% reduction in mechanical pain threshold, as measured by the Von Frey test, in germ-free mice. When looking at the dorsal root ganglia of germ-free and SPF mice, we saw a 15% increase in the percentage of neurons that were TRPV1-GFP positive in germ-free mice. Conclusions Our results thus far highlight the importance of the microbiota in regulating the lineage of nociceptive neurons and the threshold of mechanical and thermal pain responses. These findings suggest a major contribution of the microbiota in shaping the neuro-immune axis, with major implications for visceral sensitization in the context of dysbiosis. My project will be looking further into the phenotype of nociceptors in germ-free mice and the effect of microbial-derived Ahr agonists on the maturation and function of colonic TRPV1+ nociceptors. My work will advance our understanding of mechanisms by which commensal bacteria regulate GI pain. Funding Agencies CIHR

Hyperalgesia and Reduced Offset Analgesia During Spinal Anesthesia.

IntroductionSpinal anesthesia induces short-term deafferentation and causes connectivity changes in brain areas involved in endogenous pain modulation. We determined whether spinal anesthesia alters pain sensitivity and offset analgesia. Offset analgesia is a manifestation of endogenous pain modulation and characterized by profound analgesia upon a small decrease in noxious stimulation.MethodsIn this randomized controlled crossover trial, static thermal pain responses and offset analgesia were obtained in 22 healthy male volunteers during spinal anesthesia and control conditions (absence of spinal anesthesia). Pain responses and offset analgesia were measured on a remote skin area above the upper level of anesthesia (C8/Th1).ResultsFollowing spinal injection of the local anesthetic, the average maximum anesthesia level was Th6. Static pain scores at C8/Th1 were higher during spinal anesthesia compared to control: 59.1 ± 15.0 mm (spinal anesthesia) versus 51.7 ± 19.7 mm (control; p = 0.03). Offset analgesia responses were decreased during spinal analgesia: pain score decrease 79 ± 27% (spinal anesthesia) versus 90 ± 17% (control; p = 0.016).DiscussionWe confirmed that spinal anesthesia-induced deafferentation causes hyperalgesic responses to noxious thermal stimulation and reduced offset analgesia at dermatomes remote and above the level of deafferentation. While these data suggest that the reduction of offset analgesia has a central origin, related to alterations in brain areas involved in inhibitory pain control, we cannot exclude alternative (peripheral) mechanisms.Trial RegistrationDutch Cochrane Center under identifier (www.trialregister.nl) NL3874.

Inhibition of NADPH oxidase within midbrain periaqueductal gray decreases pain sensitivity in Parkinson's disease via GABAergic signaling pathway.

Hypersensitive pain response is observed in patients with Parkinson's disease (PD). However, the signal pathways leading to hyperalgesia still need to be clarified. Chronic oxidative stress is one of the hallmarks of PD pathophysiology. Since the midbrain periaqueductal gray (PAG) is an important component of the descending inhibitory pathway controlling on central pain transmission, we examined the role NADPH oxidase (NOX) of the PAG in regulating exaggerated pain evoked by PD. PD was induced by central microinjection of 6-hydroxydopamine to lesion the left medial forebrain bundle of rats. Then, Western Blot analysis and ELISA were used to determine NOXs and products of oxidative stress (i.e., 8-isoprostaglandin F2alpha and 8-hydroxy-2'-deoxyguanosine). Pain responses to mechanical and thermal stimulation were further examined in control rats and PD rats. In results, among the NOXs, protein expression of NOX4 in the PAG of PD rats was significantly upregulated, thereby the products of oxidative stress were increased. Blocking NOX4 pathway in the PAG attenuated mechanical and thermal pain responses in PD rats and this was accompanied with decreasing production of oxidative stress. In addition, inhibition of NOX4 largely restored the impaired GABA within the PAG. Stimulation of GABA receptors in the PAG of PD rats also blunted pain responses. In conclusions, NOX4 activation of oxidative stress in the PAG of PD rats is likely to impair the descending inhibitory GABAergic pathways in regulating pain transmission and thereby plays a role in the development of pain hypersensitivity in PD. Inhibition of NOX4 has beneficial effects on the exaggerated pain evoked by PD.

An ICA based approach for steady-state and transient analysis of task fMRI data: Application to study of thermal pain response

BackgroundData driven analysis methods such as independent component analysis (ICA) offer the advantage of estimating subject contributions when used in a second-level analysis. With the traditionally used regression-based methods this is achieved with a design matrix that has to be specified a priori. New methodWe show that the ability of ICA to estimate subject contributions can be effectively used to perform steady-state as well as transient analysis of task functional magnetic resonance imaging (fMRI) data, which can help reveal important group differences. ResultsWe apply the method to steady-state and transient analysis of block designed thermal pain stimulated fMRI data, and identify distinct sex differences, in parts of the pain matrix: brain stem, thalamus, amygdala, frontal pole (FP), temporal pole (TP), operculum (second somatosensory cortex, SII), anterior insular (AI), dorsal anterior cingulate cortex (dACC), and default mode network (DMN). We also show that the identified regions have significant correlation with weekly exercise and anxiety. Using transient analysis, we identify regions (SII, AI, dACC, DMN) specific to female group showing difference mainly in the initial stages of the experiments. Comparison with existing methodWith exact same spatial components input in the second level, permutation analysis of linear models cannot identify any significant group difference. In addition, the proposed transient analysis cannot be realized if user is required to input a design matrix as is the case with regression-based analyses. ConclusionsThe proposed two-level ICA is an effective multi-variate analysis method for both steady-state and transient analysis of task data.

Beneficial Effects of Electroacupuncture on Neuropathic Pain Evoked by Spinal Cord Injury and Involvement of PI3K-mTOR Mechanisms.

The purpose of this study was to examine the beneficial effects of electroacupuncture (EA) on neuropathic pain evoked by spinal cord injury (SCI) and determine the underlying molecular mechanisms of these effects. SCI was induced in rats. Behavioral tests were performed to examine pain responses induced by mechanical and thermal stimulation. Western blot analysis was used to measure the protein expression of phosphorylated mammalian target of rapamycin (p-mTOR), mTOR-mediated phosphorylated ribosomal protein S6 kinase beta-1 (p-S6K1), and phosphorylated eukaryotic translation initiation factor 4E-binding protein 1 (p-4E-BP1) in the superficial dorsal horn of the spinal cord. We showed that SCI increased the expression of p-mTOR, p-S6K1, and p-4E-BP1. The EA intervention attenuated the upregulation of mTOR signaling and alleviated mechanical and thermal pain responses in SCI rats. Blocking spinal mTOR by intrathecal injection of rapamycin also inhibited mechanical and thermal pain. In addition, blocking spinal phosphorylated phosphatidylinositide 3-kinase (p-PI3K) pathway attenuated p-mTOR pathways and mechanical and thermal hyperalgesia in SCI rats. EA also decreased the enhanced p-PI3K in the superficial dorsal horn of SCI rats. In conclusion, findings revealed specific signaling pathways that lead to neuropathic pain in response to SCI, including activation of PI3K-mTOR signaling. Further, results link the beneficial role of EA in alleviating SCI-induced neuropathic pain to its effect on these molecular mechanisms.

Acute painful autoimmune neuropathy: A variant of Guillain-Barré syndrome.

We present a painful small-fiber neuropathy variant of Guillain-Barré syndrome characterized by antecedent infectious symptoms, hyporeflexia, and albuminocytologic dissociation. Two patients received intravenous immunoglobulin, one corticosteroids. The patients subsequently improved. Immunoglobulin G (IgG) antibodies in their acute phase sera strongly bound to murine small nerve fibers, and the binding disappeared during the convalescent phase. Serum transfer to a murine nociceptive model induced transient alteration in thermal pain responses. Our case series suggest that an acute transient immune response can be directed against small nerve fibers, and that patients so affected can exhibit features of Guillain-Barré syndrome. Muscle Nerve 57: 320-324, 2018.

New Synthesis, Structure and Analgesic Properties of Methyl 1-R-4-Methyl-2,2-Dioxo-1H-2λ⁶,1-Benzothiazine-3-Carboxylates.

According to the principles of the methodology of bioisosteric replacements a series of methyl 1-R-4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylates has been obtained as potential analgesics. In addition, a fundamentally new strategy for the synthesis of compounds of this chemical class involving the introduction of N-alkyl substituent at the final stage in 2,1-benzothiazine nucleus already formed has been proposed. Using nuclear magnetic resonance (NMR) spectroscopy, mass spectrometry and X-ray diffraction analysis it has been proven that in the DMSO/K2CO3 system the reaction of methyl 4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylate and alkyl halides leads to formation of N-substituted derivatives with good yields regardless of the structure of the alkylating agent. The peculiarities of NMR (1Н and 13С) spectra of the compounds synthesized, their mass spectrometric behavior and the spatial structure are discussed. In N-benzyl derivative the ability to form a monosolvate with methanol has been found. According to the results of the pharmacological testing conducted on the model of the thermal tail-flick it has been determined that replacement of 4-ОН-group in methyl 1-R-4-hydroxy-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylates for the methyl group is actually bioisosteric since all methyl 1-R-4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylates synthesized demonstrated a statistically significant analgesic effect. The majority of the substances can inhibit the thermal pain response much more effective than piroxicam in the same dose. Under the same conditions as an analgesic the N-methyl-substituted analog exceeds not only piroxicam, but more active meloxicam as well. Therefore, it deserves in-depth biological studies on other experimental models.

Assessment of Thermal Pain Sensation in Rats and Mice Using the Hargreaves Test.

The Hargreaves test is specifically designed to assess thermal pain sensation in rodents such as rats and mice. This test has been used in experiments involving pain sensitization or recovery of thermal pain response following neural injury and regeneration. We present here a step-by-step protocol highlighted with important notes to guide first-time users through the learning process. Additionally, we have also included representative data from a rat model of sensory denervation showing how the data can be analysed to obtain meaningful results. We hope that this protocol can also assist potential users in deciding whether the Hargreaves test is a suitable test for their experiment.

P.3.010 Endogenous plasma testosterone in healthy men is negatively associated with hippocampal serotonin receptor 4 binding

Dopamine D2/D3 receptor availability at rest and its association with individual pain perception was investigated using the [11C] raclopride PET-method in 24 female Fibromyalgia (FMS) participants with (FMS+, N=11) and without (FMS−, N=13) comorbid depression and in 17 healthy women. Thermal pain thresholds (TPT) and pain responses were assessed outside the scanner. We compared the discriminative capacity, i.e. the individual׳s capacity to discriminate between lower and higher pain intensities and the response criterion, i.e. the subject׳s tendency to report pain during noxious stimulation due to psychological factors. [11C] raclopride binding potential (BP), defined as the ratio of specifically bound non-displaceable radioligand at equilibrium (BPND) was used as measure of D2/D3 receptor availability. We found significant group effects of BPND in striatal regions (left ventral striatum, left caudate nucleus and left nucleus accumbens) between FMS+ and FMS− compared to healthy subjects. Correlational analysis showed negative associations between TPT and D2/D3 receptor availability in the left caudate nucleus in FMS-, between TPT and D2/D3 receptor availability in the right caudate nucleus in FMS + and positive associations between TPT and D2/D3 receptor availability in the left putamen and right caudate nucleus in healthy controls. The response criterion was positively associated with D2/D3 receptor availability in the right nucleus accumbens in FMS − and negatively with D2/D3 receptor availability in the left caudate nucleus in healthy controls. Finally, no significant associations between D2/D3 receptor availability and discriminative capacity in any of the groups or regions were determined. These findings provide further support for a disruption of dopaminergic neurotransmission in FMS and implicate DA as important neurochemical moderator of differences in pain perception in FMS patients with and without co-morbid depression.

Relation of dopamine receptor 2 binding to pain perception in female fibromyalgia patients with and without depression – A [11C] raclopride PET-study

Dopamine D2/D3 receptor availability at rest and its association with individual pain perception was investigated using the [11C] raclopride PET-method in 24 female Fibromyalgia (FMS) participants with (FMS+, N=11) and without (FMS−, N=13) comorbid depression and in 17 healthy women. Thermal pain thresholds (TPT) and pain responses were assessed outside the scanner. We compared the discriminative capacity, i.e. the individual׳s capacity to discriminate between lower and higher pain intensities and the response criterion, i.e. the subject׳s tendency to report pain during noxious stimulation due to psychological factors. [11C] raclopride binding potential (BP), defined as the ratio of specifically bound non-displaceable radioligand at equilibrium (BPND) was used as measure of D2/D3 receptor availability. We found significant group effects of BPND in striatal regions (left ventral striatum, left caudate nucleus and left nucleus accumbens) between FMS+ and FMS− compared to healthy subjects. Correlational analysis showed negative associations between TPT and D2/D3 receptor availability in the left caudate nucleus in FMS-, between TPT and D2/D3 receptor availability in the right caudate nucleus in FMS + and positive associations between TPT and D2/D3 receptor availability in the left putamen and right caudate nucleus in healthy controls. The response criterion was positively associated with D2/D3 receptor availability in the right nucleus accumbens in FMS − and negatively with D2/D3 receptor availability in the left caudate nucleus in healthy controls. Finally, no significant associations between D2/D3 receptor availability and discriminative capacity in any of the groups or regions were determined. These findings provide further support for a disruption of dopaminergic neurotransmission in FMS and implicate DA as important neurochemical moderator of differences in pain perception in FMS patients with and without co-morbid depression.

Sex differences in psychophysical and neurophysiological responses to pain in older adults: a cross-sectional study

BackgroundNeuroimaging studies in younger adults have demonstrated sex differences in brain processing of painful experimental stimuli. Such differences may contribute to findings that women suffer disproportionately from pain. It is not known whether sex-related differences in pain processing extend to older adults.MethodsThis cross-sectional study investigated sex differences in pain reports and brain response to pain in 12 cognitively healthy older female adults and 12 cognitively healthy age-matched older male adults (age range 65–81, median = 67). Participants underwent psychophysical assessments of thermal pain responses, functional MRI, and psychosocial assessment.ResultsWhen compared to older males, older females reported experiencing mild and moderate pain at lower stimulus intensities (i.e., exhibited greater pain sensitivity; Cohen’s d = 0.92 and 0.99, respectively, p < 0.01) yet did not report greater pain-associated unpleasantness. Imaging results indicated that, despite the lower stimulus intensities required to elicit mild pain detection in females, they exhibited less deactivations than males in regions associated with the default mode network (DMN) and in regions associated with pain affect (bilateral dorsolateral prefrontal cortex, somatomotor area, rostral anterior cingulate cortex (rACC), and dorsal ACC). Conversely, at moderate pain detection levels, males exhibited greater activation than females in several ipsilateral regions typically associated with pain sensation (e.g., primary (SI) and secondary somatosensory cortices (SII) and posterior insula). Sex differences were found in the association of brain activation in the left rACC with pain unpleasantness. In the combined sample of males and females, brain activation in the right secondary somatosensory cortex was associated with pain unpleasantness.ConclusionsCognitively healthy older adults in the sixth and seventh decades of life exhibit similar sex differences in pain sensitivity compared to those reported in younger individuals. However, older females did not find pain to be more unpleasant. Notably, increased sensitivity to mild pain in older females was reflected via less brain deactivation in regions associated with both the DMN and in pain affect. Current findings elevate the rACC as a key region associated with sex differences in reports of pain unpleasantness and brain deactivation in older adults. Also, pain affect may be encoded in SII in both older males and females.Electronic supplementary materialThe online version of this article (doi:10.1186/s13293-015-0041-y) contains supplementary material, which is available to authorized users.

PTU-019 Pain, perception and reality – comparison of comfort scores of south asian and white british patients undergoing bowel cancer screening colonoscopy:

<h3>Introduction</h3> There have been several studies suggesting South Asian patients have differing pain perception to White British patients.¹Watson <i><i>et al</i>.</i>compared hot and cold pain perception in 20 age-matched South Asian and White British volunteers, with significantly increased heat pain scores and reduced pain threshold.² Recently, Al-Hashimi <i><i>et al</i></i>showed no significant differences in post-operative pain scores and analgesia consumption in 60 South Asian patients undergoing total abdominal hysterectomy versus 60 age-matched White British controls.³ Sedation and analgesia administration is well regulated in colonoscopy practice and comparing comfort scores in similar aged South Asian and White British screening patients is of interest to bowel cancer screening programme (BCSP) centres in ethnically diverse areas. <h3>Method</h3> In 2014, colonoscopy screened individuals (BCSP) in Leicester and Kettering had their self-selected ethnic origin recorded. Comfort scores of 713 patients recorded in the Exeter online database was correlated to ethnic origin data and analysed. <h3>Results</h3> Total number of patients: 713 Difference between means: 0.26 (95% CI: 0.05–0.47) <h3>Conclusion</h3> This analysis shows mean comfort scores are significantly <i>lower</i>in South Asian patients (p = &lt;0.02). This is counter to what published literature might suggest. We reported in 2014 that South Asian patients undergoing BCSP colonoscopy have significantly lower adenoma detection rates when compared to White British patients (31.68% vs 48.09% p = &lt;0.02). ⁴Perhaps fewer adenomas requiring polypectomy lead to more straightforward colonoscopy and lower comfort scores. Whatever the explanation, this analysis shows that pain perception is complex. The interaction of patient ethnicity factors (behavioural, cultural, social and psychological) are not easily predicted and requires further study. <h3>Disclosure of interest</h3> None Declared. <h3>References</h3> Edwards CL, Fillingim RB, Keefe F. Race, ethnicity and pain. Pain 2001; 94: 133–137 Watson PJ, Latif RK, Rowbotham DJ. Ethnic differences in thermal pain responses: a comparison of South Asian and White British healthy males. Pain 2005;118:194–200 Al-Hashimi M, Scott S, Griffin-Teall N, Thompson J. Influence of ethnicity on the perception and treatment of early post-operative pain. Pain 2014. doi: 10.1177/2049463714559254 Verma AM, Lewin V, Chilton AP, de Caestecker J, Dixon A, Jameson J, Wurm P, Robinson RJ. Variations in adenoma detection rate and cancer detection rate in individuals from different ethnic groups undergoing bowel cancer screening colonoscopy. Gut 2014;<b>63</b>(Suppl 1):A122

Clonal differences in IgE antibodies affect cutaneous anaphylaxis-associated thermal sensitivity in mice

Cellular and molecular mediators of immune responses are increasingly implicated in acute and chronic pain pathophysiologies. Here we demonstrate that passive cutaneous IgE/Ag anaphylaxis provokes increased thermal sensitivity in the hind paw tissue of mice. The murine anti-DNP IgE antibodies SPE-7 and ɛ26 are known to induce differential cytokine production in bone marrow cultured mast cells in vitro without antigen challenge. We found a novel, antigen-dependent heterogeneity in the thermal pain responses elicited in the hind paws between SPE-7 and ɛ26 sensitized DNP-challenged mice. Mice experienced pronounced hind paw thermal sensitivity lasting 6h after DNP challenge when sensitized with SPE-7 but not ɛ26 IgE. The two IgE clones induced equivalent hind paw edema, neutrophil influx, cytokine production, and reduction in tissue histamine content in vivo, and bound to the same or overlapping epitopes on the DNP antigen in vitro. Therefore IgE antibodies against the same antigen can induce comparable inflammation, yet contribute to markedly different anaphylaxis-associated pain within an allergic response, suggesting that non-canonical IgE binding partners such as sensory neurons may play a role in allergy-related pain responses.