Neurobiology of Pain最新文献

{"title":"Quantitative orbital tightening for pain assessment using machine learning with DeepLabCut","authors":"Saurav Gupta,&nbsp;Akihiro Yamada,&nbsp;Jennifer Ling,&nbsp;Jianguo G. Gu","doi":"10.1016/j.ynpai.2024.100164","DOIUrl":"10.1016/j.ynpai.2024.100164","url":null,"abstract":"<div><p>Pain assessment in animal models is essential for understanding mechanisms underlying pathological pain and developing effective pain medicine. The grimace scale (GS), facial expression features in pain such as orbital tightening (OT), is a valuable measure for assessing pain in animal models. However, the classical grimace scale for pain assessment is labor-intensive, subject to subjectivity and inconsistency, and is not a quantitative measure. In the present study, we utilized machine learning with DeepLabCut to annotate the superior and inferior eyelid margins and the medial and lateral canthus of the eyes in animals’ video images. Based on the annotation, we quantified the eyelid distance and palpebral fissure width of the animals’ eyes so that the degree of OT in animals with pain could be measured and described quantitatively. We established criteria for the inclusion and exclusion of the annotated images for quantifying OT, and validated our quantitative grimace scale (qGS) in the mice with pain caused by capsaicin injections in the orofacial or hindpaw regions, the Nav1.8-ChR2 mice following orofacial noxious stimulation with laser light, and the oxaliplatin-treated mice following tactile stimulation with a von Frey filament. We showed that both the eyelid distance and the palpebral fissure width were shortened significantly in the animals in pain compared to the control animals without nociceptive stimulation. Collectively, the present study has established a quantitative orbital tightening for pain assessment in mice using DeepLabCut, providing a new tool for pain assessment in preclinical studies with mice.</p></div>","PeriodicalId":52177,"journal":{"name":"Neurobiology of Pain","volume":"16 ","pages":"Article 100164"},"PeriodicalIF":0.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2452073X24000151/pdfft?md5=e0027044a63d893559b2dd5656b285ca&pid=1-s2.0-S2452073X24000151-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142136294","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neurotensin-expressing lateral hypothalamic neurons alleviate neuropathic and inflammatory pain via neurotensin receptor signaling","authors":"Rabail Khan ,&nbsp;Beenhwa Lee ,&nbsp;Kufreobong Inyang ,&nbsp;Hope Bemis ,&nbsp;Raluca Bugescu ,&nbsp;Geoffroy Laumet ,&nbsp;Gina Leinninger","doi":"10.1016/j.ynpai.2024.100172","DOIUrl":"10.1016/j.ynpai.2024.100172","url":null,"abstract":"<div><div>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 (LHA^Nts neurons) that project to brain regions that participate in descending control of pain processing. We hypothesized that LHA^Nts neurons are an endogenous source of Nts and activating them would alleviate pain dependent on Nts signaling via NtsRs. To test this, we injected <em>Nts^Cre</em> mice in the LHA with AAVs to cre-dependently express either mCherry (Control) or the excitatory hM3Dq in LHA^Nts neurons, permitting their stimulation after treatment with the hM3Dq ligand clozapine N-oxide (CNO). Activating LHA^Nts 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 LHA^Nts neurons. Pretreatment with the Nts receptor antagonist SR142948 reduced CNO-mediated analgesia, indicating that LHA^Nts neurons alleviate chronic pain in an Nts receptor-dependent manner. Taken together these data identify LHA^Nts 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.</div></div>","PeriodicalId":52177,"journal":{"name":"Neurobiology of Pain","volume":"16 ","pages":"Article 100172"},"PeriodicalIF":0.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142537641","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An investigation on the role of oxytocin in chronic neuropathic pain in a Wistar rat model","authors":"Michaela de Kock ,&nbsp;Sean Chetty ,&nbsp;Ahmed Sherif Isa ,&nbsp;Lihle Qulu-Appiah","doi":"10.1016/j.ynpai.2024.100152","DOIUrl":"10.1016/j.ynpai.2024.100152","url":null,"abstract":"<div><p><strong><em>Introduction</em></strong> Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting side effect with ineffective preventative and curative treatment. Currently, only Duloxetine has been recommended as effective treatment for CIPN, which has shown individual-dependent, short-term analgesic effects, with limiting adverse effects and poor bioavailability. The neuropeptide, oxytocin, may offer significant analgesic and anxiolytic potential, as it exerts central and peripheral attenuating effects on nociception. However, it is unknown whether the intervention administered in a model of CIPN is an effective therapeutic alternative or adjuvant. <strong><em>Materials and Methods</em></strong> The intervention was divided into two phases. Phase 1 aimed to induce CIPN in adult Wistar rats using the chemotherapeutic agent Paclitaxel. Mechanical (electronic von Frey filament) and thermal (acetone evaporation test and Hargreaves test) hypersensitivity testing were used to evaluate changes due to the neuropathic induction. Phase 2 consisted of a 14-day intervention period with saline (o.g.), duloextine (o.g.), or oxytocin (i.n.) administered as treatment. Following the intervention, anxiety-like behaviour was assessed using the elevated plus maze (EPM) and light–dark box protocols. Analysis of peripheral plasma corticosterone, peripheral plasma oxytocin, and hypothalamic oxytocin concentrations were assessed using ELISA assays. <strong><em>Results</em></strong> The findings showed that we were able to successfully establish a model of chemotherapy-induced peripheral neuropathy during Phase 1, determined by the increase in mechanical and thermal nociceptive responses following Paclitaxel administration. Furthermore, the animals treated with oxytocin displayed a significant improvement in mechanical sensitivity over the intervention phase, indicative of an improvement in nociceptive sensitivity in the presence of neuropathic pain. Animals that received Paclitaxel and treated with oxytocin also displayed significantly greater explorative behaviour during the EPM, indicative of a reduced presence of anxiety-like behaviour. <strong><em>Conclusion</em></strong> Our results support the hypothesis that intranasally administered oxytocin may augment the analgesic and anxiolytic effects of duloxetine in a chemotherapy induced peripheral neuropathy model in a Wistar rat. Future studies should consider administering the treatments in combination to observe the potential synergistic effects.</p></div>","PeriodicalId":52177,"journal":{"name":"Neurobiology of Pain","volume":"16 ","pages":"Article 100152"},"PeriodicalIF":0.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2452073X24000035/pdfft?md5=442035faf3faa47ca01167ceecffeeb0&pid=1-s2.0-S2452073X24000035-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140097506","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Induction of long-term hyperexcitability by memory-related cAMP signaling in isolated nociceptor cell bodies","authors":"Alexis Bavencoffe ,&nbsp;Michael Y. Zhu ,&nbsp;Sanjay V. Neerukonda ,&nbsp;Kayla N. Johnson ,&nbsp;Carmen W. Dessauer ,&nbsp;Edgar T. Walters","doi":"10.1016/j.ynpai.2024.100166","DOIUrl":"10.1016/j.ynpai.2024.100166","url":null,"abstract":"<div><div>Persistent hyperactivity of nociceptors is known to contribute significantly to long-lasting sensitization and ongoing pain in many clinical conditions. It is often assumed that nociceptor hyperactivity is mainly driven by continuing stimulation from inflammatory mediators. We have tested an additional possibility: that persistent increases in excitability promoting hyperactivity can be induced by a prototypical cellular signaling pathway long known to induce late-phase long-term potentiation (LTP) of synapses in brain regions involved in memory formation. This cAMP-PKA-CREB-gene transcription-protein synthesis pathway was tested using whole-cell current clamp methods on small dissociated sensory neurons (primarily nociceptors) from dorsal root ganglia (DRGs) excised from previously uninjured (“naïve”) male rats. Six-hour treatment with the specific Gαs-coupled 5-HT4 receptor agonist, prucalopride, or with the adenylyl cyclase activator forskolin induced long-term hyperexcitability (LTH) in DRG neurons that manifested 12–24 h later as action potential (AP) discharge (ongoing activity, OA) during artificial depolarization to −45 mV, a membrane potential that is normally subthreshold for AP generation. Prucalopride treatment also induced significant long-lasting depolarization of resting membrane potential (from −69 to −66 mV), enhanced depolarizing spontaneous fluctuations (DSFs) of membrane potential, and produced trends for reduced AP threshold and rheobase. LTH was prevented by co-treatment of prucalopride with inhibitors of PKA, CREB, gene transcription, or protein synthesis. As in the induction of synaptic memory, many other cellular signals are likely to be involved. However, the discovery that this prototypical memory induction pathway can induce nociceptor LTH, along with reports that cAMP signaling and CREB activity in DRGs can induce hyperalgesic priming, suggest that early, temporary, cAMP-induced transcriptional and translational mechanisms can induce nociceptor LTH that might last for long periods. The present results also raise the question of whether reactivation of primed signaling mechanisms by re-exposure to inflammatory mediators linked to cAMP synthesis during subsequent challenges to bodily integrity can “reconsolidate” nociceptor memory, extending the duration of persistent hyperexcitability.</div></div>","PeriodicalId":52177,"journal":{"name":"Neurobiology of Pain","volume":"16 ","pages":"Article 100166"},"PeriodicalIF":0.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142323217","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The timing of the mouse hind paw incision does not influence postsurgical pain","authors":"Eleri L.F. McEachern ,&nbsp;Maria Zilic ,&nbsp;Susana G. Sotocinal ,&nbsp;Nader Ghasemlou ,&nbsp;Jeffrey S. Mogil","doi":"10.1016/j.ynpai.2024.100161","DOIUrl":"10.1016/j.ynpai.2024.100161","url":null,"abstract":"<div><p>Chronobiological approaches have emerged as tools to study pain and inflammation. Although time–of-day effects on the expression of pain after injury have been studied, it remains unaddressed whether the timing of the injury itself can alter subsequent pain behaviors. The aim of this study was to assess postsurgical pain behaviors in a mouse hind paw incision assay in a circadian-dependent manner. Incisions were made at one of four equally spaced time points over a 24-hour period, with evoked and spontaneous pain behaviors measured using the von Frey mechanical sensitivity test, Hargreaves’ radiant heat paw-withdrawal test, and the Mouse Grimace Scale. Algesiometric testing was performed in C57BL/6 mice prior to and at multiple time points after incision injury, at the same time of day, until pain resolution. No statistically significant differences were observed between groups. This study adds to the literature on circadian rhythms and their influence on pain in the pursuit of more biologically informed pre- and postoperative care.</p></div>","PeriodicalId":52177,"journal":{"name":"Neurobiology of Pain","volume":"16 ","pages":"Article 100161"},"PeriodicalIF":0.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2452073X24000126/pdfft?md5=45cbc5cc70c3527e23264fe25bc82b00&pid=1-s2.0-S2452073X24000126-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141940518","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The pace of biological aging significantly mediates the relationship between internalized stigma of chronic pain and chronic low back pain severity among non-hispanic black but not non-hispanic white adults","authors":"Khalid W. Freij ,&nbsp;Fiona B.A.T. Agbor ,&nbsp;Kiari R. Kinnie ,&nbsp;Vinodh Srinivasasainagendra ,&nbsp;Tammie L. Quinn ,&nbsp;Hemant K. Tiwari ,&nbsp;Robert E. Sorge ,&nbsp;Burel R. Goodin ,&nbsp;Edwin N. Aroke","doi":"10.1016/j.ynpai.2024.100170","DOIUrl":"10.1016/j.ynpai.2024.100170","url":null,"abstract":"<div><div>This study aimed to determine the nature of the relationship between the internalized stigma of chronic pain (ISCP), the pace of biological aging, and racial disparities in nonspecific chronic low back pain (CLBP). We used Dunedin Pace of Aging from the Epigenome (DunedinPACE), Horvath’s, Hannum’s, and PhenoAge clocks to determine the pace of biological aging in adults, ages 18 to 82 years: 74 no pain, 56 low-impact pain, and 76 high-impact pain. Individuals with high-impact pain reported higher levels of ISCP and DunedinPACE compared to those with low-impact or no pain (p &lt; 0.001). There was no significant relationship between ISCP and epigenetic age acceleration from Horvath, Hannum, and PhenoAge clocks (<em>p</em> &gt; 0.05). Mediation analysis showed that an association between ISCP and pain severity and interference was mediated by the pace of biological aging (<em>p</em> ≤ 0.001). We further found that race moderated the indirect effect of ISCP on pain severity and interference, with ISCP being a stronger positive predictor of the pace of biological aging for non-Hispanic Blacks (NHBs) than for non-Hispanic Whites (NHWs). Future bio-behavioral interventions targeting internalized stigma surrounding chronic pain at various levels are necessary. A deeper understanding of the biological aging process could lead to improvements in managing nonspecific chronic low back pain (CLBP), particularly within underserved minority populations.</div></div>","PeriodicalId":52177,"journal":{"name":"Neurobiology of Pain","volume":"16 ","pages":"Article 100170"},"PeriodicalIF":0.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142533682","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Is exercise therapy the first-line treatment for chronic pain?","authors":"Emiko Senba","doi":"10.1016/j.ynpai.2024.100154","DOIUrl":"10.1016/j.ynpai.2024.100154","url":null,"abstract":"","PeriodicalId":52177,"journal":{"name":"Neurobiology of Pain","volume":"15 ","pages":"Article 100154"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2452073X24000059/pdfft?md5=aed02ef2d1dea3e3b637ab7c3e690d22&pid=1-s2.0-S2452073X24000059-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140407502","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A review of dorsal root ganglia and primary sensory neuron plasticity mediating inflammatory and chronic neuropathic pain","authors":"Kyeongran Jang,&nbsp;Sandra M. Garraway","doi":"10.1016/j.ynpai.2024.100151","DOIUrl":"10.1016/j.ynpai.2024.100151","url":null,"abstract":"<div><p>Pain is a sensory state resulting from complex integration of peripheral nociceptive inputs and central processing. Pain consists of adaptive pain that is acute and beneficial for healing and maladaptive pain that is often persistent and pathological. Pain is indeed heterogeneous, and can be expressed as nociceptive, inflammatory, or neuropathic in nature. Neuropathic pain is an example of maladaptive pain that occurs after spinal cord injury (SCI), which triggers a wide range of neural plasticity. The nociceptive processing that underlies pain hypersensitivity is well-studied in the spinal cord. However, recent investigations show maladaptive plasticity that leads to pain, including neuropathic pain after SCI, also exists at peripheral sites, such as the dorsal root ganglia (DRG), which contains the cell bodies of sensory neurons. This review discusses the important role DRGs play in nociceptive processing that underlies inflammatory and neuropathic pain. Specifically, it highlights nociceptor hyperexcitability as critical to increased pain states. Furthermore, it reviews prior literature on glutamate and glutamate receptors, voltage-gated sodium channels (VGSC), and brain-derived neurotrophic factor (BDNF) signaling in the DRG as important contributors to inflammatory and neuropathic pain. We previously reviewed BDNF’s role as a bidirectional neuromodulator of spinal plasticity. Here, we shift focus to the periphery and discuss BDNF-TrkB expression on nociceptors, non-nociceptor sensory neurons, and non-neuronal cells in the periphery as a potential contributor to induction and persistence of pain after SCI. Overall, this review presents a comprehensive evaluation of large bodies of work that individually focus on pain, DRG, BDNF, and SCI, to understand their interaction in nociceptive processing.</p></div>","PeriodicalId":52177,"journal":{"name":"Neurobiology of Pain","volume":"15 ","pages":"Article 100151"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2452073X24000023/pdfft?md5=08c83cca77407d35cd8633c8460651e0&pid=1-s2.0-S2452073X24000023-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139517322","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pain-sensorimotor interactions: New perspectives and a new model","authors":"Greg M. Murray ,&nbsp;Barry J. Sessle","doi":"10.1016/j.ynpai.2024.100150","DOIUrl":"10.1016/j.ynpai.2024.100150","url":null,"abstract":"<div><p>How pain and sensorimotor behavior interact has been the subject of research and debate for many decades. This article reviews theories bearing on pain-sensorimotor interactions and considers their strengths and limitations in the light of findings from experimental and clinical studies of pain-sensorimotor interactions in the spinal and craniofacial sensorimotor systems. A strength of recent theories is that they have incorporated concepts and features missing from earlier theories to account for the role of the sensory-discriminative, motivational-affective, and cognitive-evaluative dimensions of pain in pain-sensorimotor interactions. Findings acquired since the formulation of these recent theories indicate that additional features need to be considered to provide a more comprehensive conceptualization of pain-sensorimotor interactions. These features include biopsychosocial influences that range from biological factors such as genetics and epigenetics to psychological factors and social factors encompassing environmental and cultural influences. Also needing consideration is a mechanistic framework that includes other biological factors reflecting nociceptive processes and glioplastic and neuroplastic changes in sensorimotor and related brain and spinal cord circuits in acute or chronic pain conditions. The literature reviewed and the limitations of previous theories bearing on pain-sensorimotor interactions have led us to provide new perspectives on these interactions, and this has prompted our development of a new concept, the Theory of Pain-Sensorimotor Interactions (TOPSMI) that we suggest gives a more comprehensive framework to consider the interactions and their complexity. This theory states that <strong><em>pain is associated with plastic changes in the central nervous system (CNS) that lead to an activation pattern of motor units that contributes to the individual’s adaptive sensorimotor behavior. This activation pattern takes account of the biological, psychological, and social influences on the musculoskeletal tissues involved in sensorimotor behavior and on the plastic changes and the experience of pain in that individual. The pattern is normally optimized in terms of biomechanical advantage and metabolic cost related to the features of the individual’s musculoskeletal tissues and aims to minimize pain and any associated sensorimotor changes, and thereby maintain homeostasis. However, adverse biopsychosocial factors and their interactions may result in plastic CNS changes leading to less optimal, even maladaptive, sensorimotor changes producing motor unit activation patterns associated with the development of further pain.</em></strong> This more comprehensive theory points towards customized treatment strategies, in line with the management approaches to pain proposed in the biopsychosocial model of pain.</p></div>","PeriodicalId":52177,"journal":{"name":"Neurobiology of Pain","volume":"15 ","pages":"Article 100150"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2452073X24000011/pdfft?md5=7c27b7d26972c1b32b2102ac81886c3d&pid=1-s2.0-S2452073X24000011-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139506162","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spinal cord injury-induced neurogenic bowel: A role for host-microbiome interactions in bowel pain and dysfunction","authors":"Adam B. Willits ,&nbsp;Leena Kader ,&nbsp;Olivia Eller ,&nbsp;Emily Roberts ,&nbsp;Bailey Bye ,&nbsp;Taylor Strope ,&nbsp;Bret D. Freudenthal ,&nbsp;Shahid Umar ,&nbsp;Sree Chintapalli ,&nbsp;Kartik Shankar ,&nbsp;Dong Pei ,&nbsp;Julie Christianson ,&nbsp;Kyle M. Baumbauer ,&nbsp;Erin E. Young","doi":"10.1016/j.ynpai.2024.100156","DOIUrl":"https://doi.org/10.1016/j.ynpai.2024.100156","url":null,"abstract":"<div><h3>Background and aims</h3><p>Spinal cord injury (SCI) affects roughly 300,000 Americans with 17,000 new cases added annually. In addition to paralysis, 60% of people with SCI develop neurogenic bowel (NB), a syndrome characterized by slow colonic transit, constipation, and chronic abdominal pain. The knowledge gap surrounding NB mechanisms after SCI means that interventions are primarily symptom-focused and largely ineffective. The goal of the present studies was to identify mechanism(s) that initiate and maintain NB after SCI as a critical first step in the development of evidence-based, novel therapeutic treatment options.</p></div><div><h3>Methods</h3><p>Following spinal contusion injury at T9, we observed alterations in bowel structure and function reflecting key clinical features of NB. We then leveraged tissue-specific whole transcriptome analyses (RNAseq) and fecal 16S rRNA amplicon sequencing in combination with histological, molecular, and functional (Ca²⁺ imaging) approaches to identify potential mechanism(s) underlying the generation of the NB phenotype.</p></div><div><h3>Results</h3><p>In agreement with prior reports focused on SCI-induced changes in the skin, we observed a rapid and persistent increase in expression of calcitonin gene-related peptide (CGRP) expression in the colon. This is suggestive of a neurogenic inflammation-like process engaged by antidromic activity of below-level primary afferents following SCI. CGRP has been shown to disrupt colon homeostasis and negatively affect peristalsis and colon function. As predicted, contusion SCI resulted in increased colonic transit time, expansion of lymphatic nodules, colonic structural and genomic damage, and disruption of the inner, sterile intestinal mucus layer corresponding to increased CGRP expression in the colon. Gut microbiome colonization significantly shifted over 28 days leading to the increase in <em>Anaeroplasma,</em> a pathogenic, gram-negative microbe. Moreover, colon specific vagal afferents and enteric neurons were hyperresponsive after SCI to different agonists including fecal supernatants.</p></div><div><h3>Conclusions</h3><p>Our data suggest that SCI results in overexpression of colonic CGRP which could alter colon structure and function. Neurogenic inflammatory-like processes and gut microbiome dysbiosis can also sensitize vagal afferents, providing a mechanism for visceral pain despite the loss of normal sensation post-SCI. These data may shed light on novel therapeutic interventions targeting this process to prevent NB development in patients.</p></div>","PeriodicalId":52177,"journal":{"name":"Neurobiology of Pain","volume":"15 ","pages":"Article 100156"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2452073X24000072/pdfft?md5=3dd815ed0045b8a4173ed2ba539f6627&pid=1-s2.0-S2452073X24000072-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140533825","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}