Neurobiology of Pain最新文献

{"title":"Interactive effects of pain and arousal state on heart rate and cortical activity in the mouse anterior cingulate and somatosensory cortices","authors":"Sandoval Ortega Raquel Adaia ,&nbsp;Renard Margot ,&nbsp;Cohen Michael X. ,&nbsp;Nevian Thomas","doi":"10.1016/j.ynpai.2024.100157","DOIUrl":"10.1016/j.ynpai.2024.100157","url":null,"abstract":"<div><p>Sensory disconnection is a hallmark of sleep, yet the cortex retains some ability to process sensory information. Acute noxious stimulation during sleep increases the heart rate and the likelihood of awakening, indicating that certain mechanisms for pain sensing and processing remain active. However, processing of somatosensory information, including pain, during sleep remains underexplored. To assess somatosensation in natural sleep, we simultaneously recorded heart rate and local field potentials in the anterior cingulate (ACC) and somatosensory (S1) cortices of naïve, adult male mice, while applying noxious and non-noxious stimuli to their hind paws throughout their sleep-wake cycle. Noxious stimuli evoked stronger heart rate increases in both wake and non-rapid eye movement sleep (NREMS), and resulted in larger awakening probability in NREMS, as compared to non-noxious stimulation, suggesting differential processing of noxious and non-noxious information during sleep. Somatosensory information differentially reached S1 and ACC in sleep, eliciting complex transient and sustained responses in the delta, alpha, and gamma frequency bands as well as somatosensory evoked potentials. These dynamics depended on sleep state, the behavioral response to the stimulation and stimulation intensity (non-noxious vs. noxious). Furthermore, we found a correlation of the heart rate with the gamma band in S1 in the absence of a reaction in wake and sleep for noxious stimulation. These findings confirm that somatosensory information, including nociception, is sensed and processed during sleep even in the absence of a behavioral response.</p></div>","PeriodicalId":52177,"journal":{"name":"Neurobiology of Pain","volume":"15 ","pages":"Article 100157"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2452073X24000084/pdfft?md5=1d867902815cd56c53eb4fb7bf001383&pid=1-s2.0-S2452073X24000084-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140788448","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":"Thermal escape box: A cost-benefit evaluation paradigm for investigating thermosensation and thermal pain","authors":"Jacquelyn R. Dayton ,&nbsp;Jose Marquez ,&nbsp;Alejandra K. Romo ,&nbsp;Yi-Je Chen ,&nbsp;Jorge E. Contreras ,&nbsp;Theanne N. Griffith","doi":"10.1016/j.ynpai.2024.100155","DOIUrl":"https://doi.org/10.1016/j.ynpai.2024.100155","url":null,"abstract":"<div><p>Thermosensation, the ability to detect and estimate temperature, is an evolutionarily conserved process that is essential for survival. Thermosensing is impaired in various pain syndromes, resulting in thermal allodynia, the perception of an innocuous temperature as painful, or thermal hyperalgesia, an exacerbated perception of a painful thermal stimulus. Several behavioral assays exist to study thermosensation and thermal pain in rodents, however, most rely on reflexive withdrawal responses or the subjective quantification of spontaneous nocifensive behaviors. Here, we created a new apparatus, the thermal escape box, which can be attached to temperature-controlled plates and used to assess temperature-dependent effort-based decision-making. The apparatus consists of a light chamber with an opening that fits around temperature-controlled plates, and a small entryway into a dark chamber. A mouse must choose to stay in a brightly lit aversive area or traverse the plates to escape to the enclosed dark chamber. We quantified escape latencies of adult C57Bl/6 mice at different plate temperatures from video recordings and found they were significantly longer at 5 °C, 18 °C, and 52 °C, compared to 30 °C, a mouse’s preferred ambient temperature. Differences in escape latencies were abolished in male Trpm8^−/− mice and in male Trpv1^−/− animals. Finally, we show that chronic constriction injury procedures or oxaliplatin treatement significantly increased escape latencies at cold temperatures compared to controls, the later of which was prevented by the analgesic meloxicam. This demonstrates the utility of this assay in detecting cold pain. Collectively, our study has identified a new and effective tool that uses cost-benefit valuations to study thermosensation and thermal pain.</p></div>","PeriodicalId":52177,"journal":{"name":"Neurobiology of Pain","volume":"15 ","pages":"Article 100155"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2452073X24000060/pdfft?md5=dabe2e0a6bc09d3753d5d78632ccb495&pid=1-s2.0-S2452073X24000060-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140350865","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":"Desipramine induces anti-inflammatory dorsal root ganglion transcriptional signatures in the murine spared nerve injury model","authors":"Randal A. Serafini ,&nbsp;Aarthi Ramakrishnan ,&nbsp;Li Shen ,&nbsp;Venetia Zachariou","doi":"10.1016/j.ynpai.2024.100153","DOIUrl":"https://doi.org/10.1016/j.ynpai.2024.100153","url":null,"abstract":"<div><p>Monoamine-targeting antidepressants serve as frontline medications for chronic pain and associated comorbidities. While persistent anti-allodynic properties of antidepressants generally require weeks of treatment, several groups have demonstrated acute analgesic effects within hours of administration, suggesting a role in non-mesocorticolimbic pain processing regions such as the peripheral nervous system. To further explore this possibility, after four weeks of spared nerve injury or sham surgeries, we systemically administered desipramine or saline for an additional three weeks and performed whole transcriptome RNA sequencing on L3-6 dorsal root ganglia. Along with alterations in molecular pathways associated with neuronal activity, we observed a robust immunomodulatory transcriptional signature in the desipramine treated group. Cell subtype deconvolution predicted that these changes were associated with A- and C-fibers. Of note, differentially expressed genes from the dorsal root ganglia of DMI-treated, injured mice were largely unique compared to those from the nucleus accumbens of the same animals. These observations suggest that, under peripheral nerve injury conditions, desipramine induces specific gene expression changes across various regions of the nociceptive circuitry.</p></div>","PeriodicalId":52177,"journal":{"name":"Neurobiology of Pain","volume":"15 ","pages":"Article 100153"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2452073X24000047/pdfft?md5=d65d525a01a8a6d98785e12760320e17&pid=1-s2.0-S2452073X24000047-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140190896","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":"Massage-like stroking produces analgesia in mice","authors":"Zachary M.S. Waarala ,&nbsp;Logan Comins ,&nbsp;Sophie Laumet ,&nbsp;Joseph K. Folger ,&nbsp;Geoffroy Laumet","doi":"10.1016/j.ynpai.2023.100149","DOIUrl":"10.1016/j.ynpai.2023.100149","url":null,"abstract":"<div><p>Chronic pain treatment remains a major challenge and pharmacological interventions are associated with important side effects. Manual medicine treatments such as massage, acupuncture, manipulation of the fascial system (MFS), and osteopathic manipulative treatments produce pain relief in humans, but the underlying mechanism is poorly understood limiting leverage and optimization of manual medicine techniques as safe pain therapy. To decipher the physiological mechanisms of manipulative medicine treatments, we have established a preclinical model. Here, we established a murine model of massage-like stroking (MLS)-induced analgesia. We characterized that the analgesia effects were present in both sexes, and were independent of the experimenters, handling, consciousness, and opioid receptors. MLS alleviates thermal pain in naive mice and postoperative pain hypersensitivity. This novel model will allow discovery of the physiological mechanisms involved in MLS-induced analgesia and identification of new therapeutic strategies.</p></div>","PeriodicalId":52177,"journal":{"name":"Neurobiology of Pain","volume":"15 ","pages":"Article 100149"},"PeriodicalIF":0.0,"publicationDate":"2023-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2452073X23000363/pdfft?md5=f8237574284af1873e7905191ae13bb8&pid=1-s2.0-S2452073X23000363-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139027257","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":"Low-intensity pulsed ultrasound phonophoresis with diclofenac alleviated inflammation and pain via downregulation of M1 macrophages in rats with carrageenan-induced knee joint arthritis","authors":"Ryo Sasaki ,&nbsp;Junya Sakamoto ,&nbsp;Yuichiro Honda ,&nbsp;Satoko Motokawa ,&nbsp;Hideki Kataoka ,&nbsp;Tomoki Origuchi ,&nbsp;Minoru Okita","doi":"10.1016/j.ynpai.2023.100148","DOIUrl":"10.1016/j.ynpai.2023.100148","url":null,"abstract":"<div><h3>Objective</h3><p>This study aimed to investigate the effects of low-intensity pulsed ultrasound (LIPUS) phonophoresis with diclofenac on inflammation and pain in the acute phase of carrageenan-induced arthritis in rats.</p></div><div><h3>Design</h3><p>60 male Wistar rats were randomly divided into the arthritis, diclofenac, LIPUS, phonophoresis, and sham-arthritis control groups. LIPUS and transdermal diclofenac gel were applied to the lateral side of the inflamed knee for 7 days, initiated postinjection day 1. In the phonophoresis group, diclofenac gel was rubbed onto the skin, followed by LIPUS application over the medication. Knee joint transverse diameters, pressure pain thresholds (PPTs), and paw withdrawal thresholds (PWT) were evaluated. The number of CD68-, CD11c-, and CD206-positive cells, and IL-1β and COX-2 mRNA expression were analyzed 8 days after injection.</p></div><div><h3>Results</h3><p>In the phonophoresis group, the transverse diameter, PPT, PWT significantly recovered at the day 8 compared to those in the LIPUS and diclofenac groups. The number of CD68- and CD11c-positive cells in the phonophoresis group was significantly lower than that in the LIPUS and diclofenac groups, but no significant differences were observed among three groups in CD206-positive cells. IL-1β and COX-2 mRNA levels were lower in the phonophoresis group than in the arthritis group, although there were no differences among the LIPUS, diclofenac, and phonophoresis groups.</p></div><div><h3>Conclusion</h3><p>LIPUS phonophoresis with diclofenac is more effective to ameliorate inflammation and pain compared to diclofenac or LIPUS alone, and the mechanism involves the decrease of M1 macrophages.</p></div>","PeriodicalId":52177,"journal":{"name":"Neurobiology of Pain","volume":"15 ","pages":"Article 100148"},"PeriodicalIF":0.0,"publicationDate":"2023-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2452073X23000351/pdfft?md5=36d1e1ea99ee9ec31cf3b62e82f7fc75&pid=1-s2.0-S2452073X23000351-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138515099","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":"Percutaneous electric nerve field stimulation alters cortical thickness in a pilot study of veterans with fibromyalgia","authors":"Anna Woodbury ,&nbsp;Lisa C. Krishnamurthy ,&nbsp;Anastasia Bohsali ,&nbsp;Venkatagiri Krishnamurthy ,&nbsp;Jeremy L. Smith ,&nbsp;Melat Gebre ,&nbsp;Kari Tyler ,&nbsp;Mark Vernon ,&nbsp;Bruce Crosson ,&nbsp;Jerry P. Kalangara ,&nbsp;Vitaly Napadow ,&nbsp;Jason W. Allen ,&nbsp;Daniel Harper","doi":"10.1016/j.ynpai.2022.100093","DOIUrl":"10.1016/j.ynpai.2022.100093","url":null,"abstract":"<div><h3>Objective</h3><p>To evaluate changes in cortical thickness and right posterior insula (r-pIns) gamma-aminobutyric acid (GABA) concentrations in veterans with fibromyalgia treated with auricular percutaneous electric nerve field stimulation (PENFS).</p></div><div><h3>Materials &amp; methods</h3><p>This was a randomized, controlled, open label investigation conducted in a government hospital. Twenty-one<!--> <!-->veterans with fibromyalgia were<!--> <!-->randomized to receive either standard therapy (ST; i.e., 4 weekly visits with a pain practitioner) or ST with<!--> <!-->auricular PENFS (ST + PENFS). Neuroimaging data was collected at baseline (i.e. before the first treatment session) and again within 2 weeks post-treatment.​ Clinical pain and physical function were also assessed at<!--> <!-->these timepoints. Single-voxel magnetic resonance spectroscopy was carried out in r-pIns to assess changes in r-pIns GABA concentrations and high-resolution T1-weighted images were collected to assess changes in regional gray matter volume using cortical thickness.</p></div><div><h3>Results</h3><p>Both the ST + PENFS and ST groups reported a decrease in pain with treatment. <strong>Volumetric:</strong> Cortical thickness significantly decreased in the left middle posterior cingulate (p = 0.018) and increased in the left cuneus (p = 0.014) following ST + PENFS treatment. These findings were significant following FDR correction for multiple comparisons. ST group right hemisphere insula cortical thickness increased post-treatment and was significantly (p = 0.02) inversely correlated with pain scores. ST + PENFS group right hemisphere posterior dorsal cingulate size significantly (p = 0.044) positively correlated with pain scores. <strong>GABA</strong>: There were no significant correlations with GABA, though a trend was noted towards increased GABA following treatment in both groups (p = 0.083) using a linear mixed effects model.</p></div><div><h3>Conclusions</h3><p>Results suggest a novel effect of PENFS reflected by differential volumetric changes compared to ST. The changes in GABA that occur in both groups are more likely related to ST. Insular GABA and cortical thickness in key regions of interest may be developed as potential biomarkers for evaluating chronic pain pathology and treatment outcomes.</p></div>","PeriodicalId":52177,"journal":{"name":"Neurobiology of Pain","volume":"12 ","pages":"Article 100093"},"PeriodicalIF":0.0,"publicationDate":"2022-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9207563/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10347402","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":"Anandamide in the dorsal periaqueductal gray inhibits sensory input without a correlation to sympathoexcitation","authors":"Christopher J. Roberts ,&nbsp;Francis A. Hopp ,&nbsp;Quinn H. Hogan ,&nbsp;Caron Dean","doi":"10.1016/j.ynpai.2022.100104","DOIUrl":"10.1016/j.ynpai.2022.100104","url":null,"abstract":"<div><p>There is growing literature supporting cannabinoids as a potential therapeutic for pain conditions. The development of chronic pain has been associated with reduced concentrations of the endogenous cannabinoid anandamide (AEA) in the midbrain dorsal periaqueductal gray (dPAG), and microinjections of synthetic cannabinoids into the dPAG are antinociceptive. Therefore, the goal of this study was to examine the role of the dPAG in cannabinoid-mediated sensory inhibition. Given that cannabinoids in the dPAG also elicit sympathoexcitation, a secondary goal was to assess coordination between sympathetic and antinociceptive responses. AEA was microinjected into the dPAG while recording single unit activity of wide dynamic range (WDR) dorsal horn neurons (DHNs) evoked by high intensity mechanical stimulation of the hindpaw, concurrently with renal sympathetic nerve activity (RSNA), in anesthetized male rats. AEA microinjected into the dPAG decreased evoked DHN activity (n = 24 units), for half of which AEA also elicited sympathoexcitation. AEA actions were mediated by cannabinoid 1 receptors as confirmed by local pretreatment with the cannabinoid receptor antagonist AM281. dPAG microinjection of the synaptic excitant DL-homocysteic acid (DLH) also decreased evoked DHN activity (n = 27 units), but in all cases this was accompanied by sympathoexcitation. Thus, sensory inhibition elicited from the dPAG is not exclusively linked with sympathoexcitation, suggesting discrete neuronal circuits. The rostrocaudal location of sites may affect evoked responses as AEA produced sensory inhibition without sympathetic effects at 86 % of caudal compared to 25 % of rostral sites, supporting anatomically distinct neurocircuits. These data indicate that spatially selective manipulation of cannabinoid signaling could provide analgesia without potentially harmful autonomic activation.</p></div>","PeriodicalId":52177,"journal":{"name":"Neurobiology of Pain","volume":"12 ","pages":"Article 100104"},"PeriodicalIF":0.0,"publicationDate":"2022-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/6c/fd/main.PMC9755024.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10688035","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 neurobiology of social stress resulting from Racism: Implications for pain disparities among racialized minorities","authors":"Joanna M. Hobson ,&nbsp;Myles D. Moody ,&nbsp;Robert E. Sorge ,&nbsp;Burel R. Goodin","doi":"10.1016/j.ynpai.2022.100101","DOIUrl":"10.1016/j.ynpai.2022.100101","url":null,"abstract":"<div><p>Extant literature posits that humans experience two types of threat: physical threat and social threat. While describing pain as “physical” or “social” can be helpful for understanding pain origins (i.e., broken bone versus lost relationship), this dichotomy is largely artificial and not particularly helpful for understanding how the human brain experiences pain. One real world example of social exclusion and rejection that is threatening and likely to bring about significant stress is racism. Racism is a system of beliefs, practices, and policies that operates to disadvantage racialized minorities while providing advantage to those with historical power, particularly White people in the United States and most other Western nations. The objective of this Mini-Review is to present evidence in support of the argument that racism promotes physical pain in racialized minorities, which in turn promotes chronic pain disparities. First, we provide a theoretical framework describing how racism is a potent stressor that affects the health and well-being of racialized minorities. We will then address the neurobiological underpinnings linking racism to social threat, as well as that linking social threats and physical pain. Finally, we will discuss how the perception of social threat brought about by racism may undermine pain management efforts.</p></div>","PeriodicalId":52177,"journal":{"name":"Neurobiology of Pain","volume":"12 ","pages":"Article 100101"},"PeriodicalIF":0.0,"publicationDate":"2022-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9449662/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33461327","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":"Enrichment of genomic pathways based on differential DNA methylation profiles associated with knee osteoarthritis pain","authors":"Soamy Montesino-Goicolea ,&nbsp;Lingsong Meng ,&nbsp;Asha Rani ,&nbsp;Zhiguang Huo ,&nbsp;Thomas C. Foster ,&nbsp;Roger B. Fillingim ,&nbsp;Yenisel Cruz-Almeida","doi":"10.1016/j.ynpai.2022.100107","DOIUrl":"10.1016/j.ynpai.2022.100107","url":null,"abstract":"<div><p>Our study aimed to identify differentially methylated regions (i.e., genomic region where multiple adjacent CpG sites show differential methylation) and their enriched genomic pathways associated with knee osteoarthritis pain (KOA). We recruited cognitively healthy middle to older aged (age 45–85) adults with (n = 182) and without (n = 31) self-reported KOA pain. We also extracted DNA from peripheral blood that was analyzed using MethylationEPIC arrays. The R package <em>minfi</em> (<span>Aryee et al., 2014</span>) was used to perform methylation data preprocessing and quality control. To investigate biological pathways impacted by differential methylation, we performed pathway enrichment analysis using Ingenuity Pathway Analysis (IPA) to identify canonical pathways and upstream regulators. Annotated genes within ± 5 kb of the putative differentially methylated regions (DMRs, p &lt; 0.05) were subjected to the IPA analysis. There was no significant difference in age, sex, study site between no pain and pain group (p &gt; 0.05). Non-Hispanic black individuals were overrepresented in the pain group (p = 0.003). At raw p &lt; 0.05 cutoff, we identified a total of 19,710 CpG probes, including 13,951 hypermethylated CpG probes, for which DNA methylation level was higher in the groups with highest pain grades. We also identified 5,759 hypomethylated CpG probes for which DNA methylation level was lower in the pain groups with higher pain grades. IPA revealed that pain-related DMRs were enriched across multiple pathways and upstream regulators. The top 10 canonical pathways were linked to cellular signaling processes related to immune responses (i.e., antigen presentation, PD-1, PD-L1 cancer immunotherapy, B cell development, IL-4 signaling, Th1 and Th2 activation pathway, and phagosome maturation). Moreover, in terms of upstream regulators, NDUFAF3 was the most significant (p = 8.6E-04) upstream regulator. Our findings support previous preliminary work suggesting the importance of epigenetic regulation of the immune system in knee pain and the need for future work to understand the epigenetic contributions to chronic pain.</p></div>","PeriodicalId":52177,"journal":{"name":"Neurobiology of Pain","volume":"12 ","pages":"Article 100107"},"PeriodicalIF":0.0,"publicationDate":"2022-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9755025/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10638422","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":"Sex-distinct microglial activation and myeloid cell infiltration in the spinal cord after painful peripheral injury","authors":"Nolan A. Huck ,&nbsp;Lauren J. Donovan ,&nbsp;Huaishuang Shen ,&nbsp;Claire E. Jordan ,&nbsp;Gabriella P.B. Muwanga ,&nbsp;Caldwell M. Bridges ,&nbsp;Thomas E. Forman ,&nbsp;Stephanie A. Cordonnier ,&nbsp;Elena S. Haight ,&nbsp;Fiona Dale-Huang ,&nbsp;Yoshinori Takemura ,&nbsp;Vivianne L. Tawfik","doi":"10.1016/j.ynpai.2022.100106","DOIUrl":"10.1016/j.ynpai.2022.100106","url":null,"abstract":"<div><p>Chronic pain is a common and often debilitating problem that affects 100 million Americans. A better understanding of pain’s molecular mechanisms is necessary for developing safe and effective therapeutics. Microglial activation has been implicated as a mediator of chronic pain in numerous preclinical studies; unfortunately, translational efforts using known glial modulators have largely failed, perhaps at least in part due to poor specificity of the compounds pursued, or an incomplete understanding of microglial reactivity. In order to achieve a more granular understanding of the role of microglia in chronic pain as a means of optimizing translational efforts, we utilized a clinically-informed mouse model of complex regional pain syndrome (CRPS), and monitored microglial activation throughout pain progression. We discovered that while both males and females exhibit spinal cord microglial activation as evidenced by increases in Iba1, activation is attenuated and delayed in females. We further evaluated the expression of the newly identified microglia-specific marker, TMEM119, and identified two distinct populations in the spinal cord parenchyma after peripheral injury: TMEM119+ microglia and TMEM119- infiltrating myeloid lineage cells, which are comprised of Ly6G + neutrophils and Ly6G- macrophages/monocytes. Neurons are sensitized by inflammatory mediators released in the CNS after injury; however, the cellular source of these cytokines remains somewhat unclear. Using multiplex <em>in situ</em> hybridization in combination with immunohistochemistry, we demonstrate that spinal cord TMEM119+ microglia are the cellular source of cytokines IL6 and IL1β after peripheral injury. Taken together, these data have important implications for translational studies: 1) microglia remain a viable analgesic target for males and females, so long as duration after injury is considered; 2) the analgesic properties of microglial modulators are likely at least in part related to their suppression of microglial-released cytokines, and 3) a limited number of neutrophils and macrophages/monocytes infiltrate the spinal cord after peripheral injury but have unknown impact on pain persistence or resolution. Further studies to uncover glial-targeted therapeutic interventions will need to consider sex, timing after injury, and the exact target population of interest to have the specificity necessary for translation.</p></div>","PeriodicalId":52177,"journal":{"name":"Neurobiology of Pain","volume":"12 ","pages":"Article 100106"},"PeriodicalIF":0.0,"publicationDate":"2022-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/f8/b4/main.PMC9755061.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9517375","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}