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Up to 20% of people worldwide develop gastrointestinal symptoms following a meal, leading to decreased quality of life, substantial morbidity and high medical costs. Although the interest of both the scientific and lay communities in this issue has increased markedly in recent years, with the worldwide introduction of gluten-free and other diets, the underlying mechanisms of food-induced abdominal complaints remain largely unknown. Here we show that a bacterial infection and bacterial toxins can trigger an immune response that leads to the production of dietary-antigen-specific IgE antibodies in mice, which are limited to the intestine. Following subsequent oral ingestion of the respective dietary antigen, an IgE- and mast-cell-dependent mechanism induced increased visceral pain. This aberrant pain signalling resulted from histamine receptor H-mediated sensitization of visceral afferents. Moreover, injection of food antigens (gluten, wheat, soy and milk) into the rectosigmoid mucosa of patients with irritable bowel syndrome induced local oedema and mast cell activation. Our results identify and characterize a peripheral mechanism that underlies food-induced abdominal pain, thereby creating new possibilities for the treatment of irritable bowel syndrome and related abdominal pain disorders.
Learn More >Background: Chronic low back pain is the most prevalent chronic pain condition worldwide and access to behavioral pain treatment is limited. Virtual reality (VR) is an immersive technology that may provide effective behavioral therapeutics for chronic pain.
Learn More >Serotonin (5-HT) acts as a neurotransmitter in the central nervous system (CNS) and as a mediator released by enterochromaffin cells to regulate intestinal motility. However, this amine also plays an important role as an inflammatory mediator and induces phenotypic changes of nociceptors. Despite the wide knowledge of the role of 5-HT in nociception, most studies have focused on its role in the CNS, while a clear information about its role in peripheral tissues is still lacking. In the present study, we investigated the role of peripheral 5-HT receptors in the nociceptive response induced by 5-HT or carrageenan in mice by using antagonists that target different 5-HT receptors. Mechanical nociceptive threshold was measured with an analgesimeter and evaluated after intraplantar (i.pl.) injection of 5-HT or carrageenan. 5-HT antagonists were injected via the i.pl. route. 5-HT (10, 20, 40 or 80 μg/paw) or carrageenan (100 μg/paw) induced mechanical allodynia. Pretreatment with isamoltane (5 μg; 5-HT antagonist) or ketanserine (1 μg; 5-HT antagonist) did not affect the mechanical allodynia induced by 5-HT. This response was inhibited by BRL 15572 (10 μg; 5-HT antagonist) or SB 269970 (25 μg; 5-HT antagonist). On the other hand, mechanical allodynia induced by 5-HT or carrageenan was exacerbated by ondansetron (10, 20 or 40 μg; 5-HT antagonist). The results indicate that activation of 5-HT and 5-HT receptors plays a role in the mechanical allodynia induced by 5-HT in mice. This study also demonstrates the inhibitory role of peripheral 5-HT receptors in the nociceptive response induced by 5-HT or carrageenan.
Learn More >UVB irradiation induces hyperalgesia in human and animal pain models. We investigated mechanical sensitization, increase in axonal excitability and spontaneous activity in different C-nociceptor classes following UVB in pig skin. We focused on units with receptive fields covering both irradiated and non-irradiated skin allowing intra-individual comparisons. 35 pigs were irradiated in a chessboard pattern and extracellular single-fibre recordings were obtained 10-28 h later (152 fibers). Units from the contralateral hindlimb served as control (n=112). Irradiated and non-irradiated parts of the same innervation territory were compared in 36 neurons: low threshold C-touch fibers (n=10) and sympathetic efferents (n=2) were unchanged, but lower mechanical thresholds and higher discharge frequency at threshold were found in mechanosensitive nociceptors (n=12). Half of them could be activated with non-noxious brush stimuli in the sunburn. 4 of 12 mechano-insensitive nociceptors were found sensitized to mechanical stimulation in the irradiated part of the receptive field. Activity dependent slowing of conduction was reduced in the irradiated and in the non-irradiated skin as compared to the control leg whereas increased ability to follow high stimulation frequencies was restricted to the sunburn (108.5 ± 37 Hz UVB vs. 6.3 ± 1 Hz control). Spontaneous activity was more frequent in the sunburn (72/152 vs. 31/112). Mechanical sensitization of primary nociceptors and higher maximum following frequency are suggested to contribute to primary hyperalgesia, whereas spontaneous activity of silent nociceptors might offer a mechanistic link contributing to ongoing pain and facilitated induction of spinal sensitization.
Learn More >While knee and hip replacements are intended to relieve pain and improve function, up to 44% of knee replacement patients and 27% of hip replacement patients report persistent postoperative joint pain. Improving surgical pain management is essential. We conducted a single-site, three-arm, parallel-group randomized clinical trial conducted at an orthopedic clinic, among patients undergoing total joint arthroplasty (TJA) of the hip or knee. Mindfulness meditation (MM), hypnotic suggestion (HS), and cognitive-behavioral pain psychoeducation (CBE) were each delivered in a single, 15-minute group session as part of a 2-hour, preoperative education program. Preoperative outcomes – pain intensity, pain unpleasantness, pain medication desire, and anxiety – were measured with numeric rating scales. Postoperative physical functioning at 6-week follow-up was assessed with the Patient-Reported Outcomes Measurement Information System Physical Function computer adaptive test. TJA patients were randomized to preoperative MM, HS, or CBE (n=285). MM and HS led to significantly less preoperative pain intensity, pain unpleasantness, and anxiety. MM also decreased preoperative pain medication desire relative to CBE and increased postoperative physical functioning at 6-week follow-up relative to HS and CBE. Moderation analysis revealed surgery type did not differentially impact the three interventions. Thus, a single session of a simple, scripted MM intervention may be able to immediately decrease TJA patients' preoperative clinical symptomology and improve postoperative physical function. As such, embedding brief MM interventions in surgical care pathways has the potential to improve surgical outcomes for the millions of patients receiving TJA each year.
Learn More >Pain is a frequent reason for patients to ask for medical services. However, systematic information about the extent and impact of pain, especially in developing countries, has not been available up to now. We evaluated, whether the 11th edition of the ICD can fill this gap by coding all electronic out-patient medical records of the pain clinic at Siriraj Hospital in Thailand in 2019 (8714 visits), using the ICD-10 and ICD-11 browsers referenced on the WHO websites. The three most frequent pain-related codes in ICD-10 were R52.2 "Other chronic pain" (29%), M54.5 "Low back pain" (18%), and M79.6 "Pain in limb" (13%). In ICD-11, the three most frequent codes were MG30.31 "Chronic secondary musculoskeletal pain associated with structural changes" (28%), MG30.51 "Chronic peripheral neuropathic pain" (26%), and MG30.10 "Chronic cancer pain" (23%). Thus, using the currently valid ICD-10 system, roughly one third of patient encounters were coded as "Other chronic pain", and the next two were specifying the pain region rather than any underlying cause. In contrast, ICD-11 coding of the same patients identified underlying causes (bones and joints, somatosensory nervous system, cancer or surgery), which provide guidance towards differential patient management. In our pain clinic, a majority of patients suffered from Chronic cancer pain, Chronic neuropathic pain, and Chronic secondary musculoskeletal pain, which were poorly defined or non-existent in the current ICD-10 coding system. Compared to the ICD-10, the ICD-11 provides more detailed diagnostic categories and is more informative for clinical use, research and resource allocation for pain-related conditions.
Learn More >It remains unknown why upon similar acute/subacute painful conditions, pain persists in some individuals while in others it resolves. Genetic factors, mood, and functional alterations, particularly involving the mesolimbic network, appear to be key. In order to explore potential susceptibility/resistance factors, we screened a large population of rats with a peripheral neuropathy and we isolated a small subset (<15%) that presented high thresholds (HT) to mechanical allodynia (reduced pain manifestation). The phenotype was sustained over 12 weeks and was associated with higher hedonic behavior when compared with low threshold subjects (LT). The nucleus accumbens (NAc) of HT and LT animals were isolated for proteomic analysis by Sequential Window Acquisition of All Theoretical Mass Spectra (SWATH-MS). Two hundred and seventy-nine proteins displayed different expression between LT and HT animals/subjects. Among several protein families, the proteasome pathway repeatedly emerged in gene ontology enrichment and KEGG analyses. Several alpha and beta 20S proteasome subunits were increased in LT when compared to HT animals (e.g., PSMα1, PSMα2, and PSMβ5). On the contrary, UBA6, an upstream ubiquitin-activating enzyme, was decreased in LT animals. Altogether these observations are consistent with an overactivation of the accumbal proteasome pathway in animals that manifest pain and depressive-like behaviors after a neuropathic injury. All the proteomic data are available via ProteomeXchange with identifier PXD022478.
Learn More >Existing studies on cognitive impairments in chronic pain do not investigate peripheral neuropathic pain (PNP) or compare pain conditions in a satisfactory manner. Here we aimed to compare executive dysfunctions in PNP patients with fibromyalgia (FM) and healthy controls (HC). Patients who self-reported cognitive impairments were assessed according to criteria for PNP or FM. Seventy-three patients met criteria and completed testing on executive functioning and IQ measures. We also included twenty matched healthy controls. Regression models controlling for age, sex and IQ, tested associations between group category (PNP, FM or HC) and outcomes. If a substantial association was detected, we followed up with head-to-head comparisons between PNP and FM. Multivariate regression models then tested associations between executive functioning and pain type, controlling for significant confounders. Results from head-to-head comparison between pain conditions showed significant differences on years lived with pain (FM > PNP), the use of anticonvulsants (PNP > FM) and use of analgesics (PNP > FM). When controlled for all significant differences, PNP patients had significantly lower scores on an attention-demanding cued-recall task compared to FM. Poor performance on attention-demanding cued-recall task was associated with PNP, which translate into problems with retaining fast-pace or advanced information.
Learn More >Medical outcomes are strongly affected by placebo and nocebo effects. Prediction of who responds to such expectation effects has proven to be challenging. Most recent approaches to prediction have focused on placebo effects in the context of previous treatment experiences and expectancies, or personality traits. However, a recent model has suggested that basic somatosensory characteristics play an important role in expectation responses. Consequently, this study investigated not only the role of psychological variables, but also of basic somatosensory characteristics. In this study, 624 participants underwent a placebo and nocebo heat pain paradigm. Additionally, individual psychological and somatosensory characteristics were assessed. While no associations were identified for placebo responses, nocebo responses were associated with personality traits (e.g. neuroticism) and somatosensory characteristics (e.g. thermal pain threshold). Importantly, the associations between somatosensory characteristics and nocebo responses were among the strongest. This study shows that apart from personality traits, basic somatosensory characteristics play an important role in individual nocebo responses, in agreement with the novel idea that nocebo responses result from the integration of top-down expectation and bottom-up sensory information.
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