Pub Date : 2024-07-01DOI: 10.1016/j.ynpai.2024.100158
Annabel Vetterlein , Thomas Plieger , Merlin Monzel , Svea A. Hogeterp , Lilli Wagner , Thomas Grünhage , Andrea Felten , Peter Trautner , Jana Karneboge , Martin Reuter
In clinical assessments and pain therapy, patients are asked to imagine themselves in pain. However, the underlying neuronal processes remain poorly understood. Prior research has focused on empathy for pain or reported small sample sizes. Thus, the present study aimed to promote the neurobiological understanding of self-referential pain imagination. We hypothesised to find activation contrasts (pain vs. no pain) across pain-related areas and expected two of the most prominent predictors of chronic pain, pain sensitivity (PS) and locus of control (LoC), to be moderators.
In an fMRI study, N = 82 participants completed a pain imagination task, in which they were asked to imagine themselves in painful and non-painful situations presented in the form of pictures and texts. After each trial, they were instructed to give painfulness ratings. As a laboratory measure of PS, electrical pain thresholds were assessed. A questionnaire was completed to measure LoC.
Across presentation modes we found activity contrasts in previously pain-related regions, such as the prefrontal, supplementary motor, primary motor, somatosensory and posterior parietal cortices, and the cerebellum. We found positive associations of PS and external LoC with painfulness ratings, and a negative correlation between PS and internal LoC. Despite our hypotheses, neither PS nor internal LoC were significant predictors of the BOLD-signal contrasts.
Though future studies are needed to draw further conclusions, our results provide preliminary evidence of a potential neuronal imagination-perception overlap in pain.
{"title":"Neuronal activation patterns during self-referential pain imagination","authors":"Annabel Vetterlein , Thomas Plieger , Merlin Monzel , Svea A. Hogeterp , Lilli Wagner , Thomas Grünhage , Andrea Felten , Peter Trautner , Jana Karneboge , Martin Reuter","doi":"10.1016/j.ynpai.2024.100158","DOIUrl":"10.1016/j.ynpai.2024.100158","url":null,"abstract":"<div><p>In clinical assessments and pain therapy, patients are asked to imagine themselves in pain. However, the underlying neuronal processes remain poorly understood. Prior research has focused on empathy for pain or reported small sample sizes. Thus, the present study aimed to promote the neurobiological understanding of self-referential pain imagination. We hypothesised to find activation contrasts (pain vs. no pain) across pain-related areas and expected two of the most prominent predictors of chronic pain, pain sensitivity (PS) and locus of control (LoC), to be moderators.</p><p>In an fMRI study, <em>N</em> = 82 participants completed a pain imagination task, in which they were asked to imagine themselves in painful and non-painful situations presented in the form of pictures and texts. After each trial, they were instructed to give painfulness ratings. As a laboratory measure of PS, electrical pain thresholds were assessed. A questionnaire was completed to measure LoC.</p><p>Across presentation modes we found activity contrasts in previously pain-related regions, such as the prefrontal, supplementary motor, primary motor, somatosensory and posterior parietal cortices, and the cerebellum. We found positive associations of PS and external LoC with painfulness ratings, and a negative correlation between PS and internal LoC. Despite our hypotheses, neither PS nor internal LoC were significant predictors of the BOLD-signal contrasts.</p><p>Though future studies are needed to draw further conclusions, our results provide preliminary evidence of a potential neuronal imagination-perception overlap in pain.</p></div>","PeriodicalId":52177,"journal":{"name":"Neurobiology of Pain","volume":"16 ","pages":"Article 100158"},"PeriodicalIF":0.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2452073X24000096/pdfft?md5=8a9c2603322477b07469a22e7aeb5eea&pid=1-s2.0-S2452073X24000096-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141784323","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}
Pub Date : 2024-07-01DOI: 10.1016/j.ynpai.2024.100167
Rayan Haroun , Samuel J. Gossage , Federico Iseppon , Alexander Fudge , Sara Caxaria , Manuel Arcangeletti , Charlotte Leese , Bazbek Davletov , James J. Cox , Shafaq Sikandar , Fraser Welsh , Iain P. Chessell , John N. Wood
Cancer pain is a growing problem, especially with the substantial increase in cancer survival. Reports indicate that bone metastasis, whose primary symptom is bone pain, occurs in 65–75% of patients with advanced breast or prostate cancer. We optimized a preclinical in vivo model of cancer-induced bone pain (CIBP) involving the injection of Lewis Lung Carcinoma cells into the intramedullary space of the femur of C57BL/6 mice or transgenic mice on a C57BL/6 background. Mice gradually reduce the use of the affected limb, leading to altered weight bearing. Symptoms of secondary cutaneous heat sensitivity also manifest themselves. Following optimization, three potential analgesic treatments were assessed; 1) single ion channel targets (targeting the voltage-gated sodium channels NaV1.7, NaV1.8, or acid-sensing ion channels), 2) silencing µ-opioid receptor-expressing neurons by modified botulinum compounds, and 3) targeting two inflammatory mediators simultaneously (nerve growth factor (NGF) and tumor necrosis factor (TNF)). Unlike global NaV1.8 knockout mice which do not show any reduction in CIBP-related behavior, embryonic conditional NaV1.7 knockout mice in sensory neurons exhibit a mild reduction in CIBP-linked behavior. Modified botulinum compounds also failed to cause a detectable analgesic effect. In contrast, inhibition of NGF and/or TNF resulted in a significant reduction in CIBP-driven weight-bearing alterations and prevented the development of secondary cutaneous heat hyperalgesia. Our results support the inhibition of these inflammatory mediators, and more strongly their dual inhibition to treat CIBP, given the superiority of combination therapies in extending the time needed to reach limb use score zero in our CIBP model.
{"title":"Novel therapies for cancer-induced bone pain","authors":"Rayan Haroun , Samuel J. Gossage , Federico Iseppon , Alexander Fudge , Sara Caxaria , Manuel Arcangeletti , Charlotte Leese , Bazbek Davletov , James J. Cox , Shafaq Sikandar , Fraser Welsh , Iain P. Chessell , John N. Wood","doi":"10.1016/j.ynpai.2024.100167","DOIUrl":"10.1016/j.ynpai.2024.100167","url":null,"abstract":"<div><div>Cancer pain is a growing problem, especially with the substantial increase in cancer survival. Reports indicate that bone metastasis, whose primary symptom is bone pain, occurs in 65–75% of patients with advanced breast or prostate cancer. We optimized a preclinical <em>in vivo</em> model of cancer-induced bone pain (CIBP) involving the injection of Lewis Lung Carcinoma cells into the intramedullary space of the femur of C57BL/6 mice or transgenic mice on a C57BL/6 background. Mice gradually reduce the use of the affected limb, leading to altered weight bearing. Symptoms of secondary cutaneous heat sensitivity also manifest themselves. Following optimization, three potential analgesic treatments were assessed; 1) single ion channel targets (targeting the voltage-gated sodium channels Na<sub>V</sub>1.7, Na<sub>V</sub>1.8, or acid-sensing ion channels), 2) silencing µ-opioid receptor-expressing neurons by modified botulinum compounds, and 3) targeting two inflammatory mediators simultaneously (nerve growth factor (NGF) and tumor necrosis factor (TNF)). Unlike global Na<sub>V</sub>1.8 knockout mice which do not show any reduction in CIBP-related behavior, embryonic conditional Na<sub>V</sub>1.7 knockout mice in sensory neurons exhibit a mild reduction in CIBP-linked behavior. Modified botulinum compounds also failed to cause a detectable analgesic effect. In contrast, inhibition of NGF and/or TNF resulted in a significant reduction in CIBP-driven weight-bearing alterations and prevented the development of secondary cutaneous heat hyperalgesia. Our results support the inhibition of these inflammatory mediators, and more strongly their dual inhibition to treat CIBP, given the superiority of combination therapies in extending the time needed to reach limb use score zero in our CIBP model.</div></div>","PeriodicalId":52177,"journal":{"name":"Neurobiology of Pain","volume":"16 ","pages":"Article 100167"},"PeriodicalIF":0.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142357105","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}
Pub Date : 2024-07-01DOI: 10.1016/j.ynpai.2024.100169
Melissa E. Lenert , Audrey R. Green , Ericka N. Merriwether , Michael D. Burton
Fibromyalgia (FM) is a complex chronic musculoskeletal pain disorder with an elusive pathogenesis, with a strong implication of immune interactions. We recently found that IL-5 and the adaptive immune system mediates pain outcomes in fibromyalgia (FM) patients and preclinical models of FM-like chronic widespread pain (CWP). However, there is an active debate if FM/CWP has an autoimmune etiology. Preclinical models of CWP utilize a repeated insult paradigm, which resembles a primary, then secondary response similarly observed in the antibody response, in which the subsequent event causes a potentiated pain response. Recent translational studies have implicated immunoglobulins (Ig) and B-cells in FM/CWP pathophysiology. To understand if these are involved in preclinical models of CWP, we performed comprehensive B-cell phenotyping in the bone marrow, circulation, and popliteal (draining) lymph nodes in the two-hit acidic saline model of CWP. We found increased MHC class II-expressing B-cells in peripheral blood, increased activated plasma cells in peripheral blood, and increased memory B-cells in the bone marrow. Interestingly, acidic pH (4.0) injected mice have reduced levels of IgG1, independent of treatment with IL-5. We have demonstrated that the acidic saline model of CWP induces T-cell mediated activation of B-cells, increased active plasma cells, and increased memory B-cells in female mice.
纤维肌痛（FM）是一种复杂的慢性肌肉骨骼疼痛疾病，其发病机制难以捉摸，与免疫相互作用有密切关系。我们最近发现，IL-5 和适应性免疫系统介导了纤维肌痛（FM）患者和 FM 类慢性广泛性疼痛（CWP）临床前模型的疼痛结果。然而，FM/CWP 是否具有自身免疫病因学还存在激烈的争论。慢性广泛性疼痛的临床前模型采用了一种重复侮辱范式，这种范式类似于抗体反应中观察到的先原发后继反应，在这种范式中，随后发生的事件会导致疼痛反应增强。最近的转化研究表明，免疫球蛋白（Ig）和 B 细胞与 FM/CWP 病理生理学有关。为了了解临床前 CWP 模型是否与这些因素有关，我们在两击酸性盐水 CWP 模型中对骨髓、血液循环和腘窝（引流）淋巴结进行了全面的 B 细胞表型分析。我们发现外周血中表达 MHC II 类的 B 细胞增多，外周血中活化浆细胞增多，骨髓中记忆性 B 细胞增多。有趣的是，注射酸性 pH 值（4.0）的小鼠 IgG1 水平降低，与 IL-5 治疗无关。我们已经证明，CWP 的酸性生理盐水模型可诱导 T 细胞介导的 B 细胞活化、活性浆细胞增加以及雌性小鼠记忆性 B 细胞增加。
{"title":"B-cell and plasma cell activation in a mouse model of chronic muscle pain","authors":"Melissa E. Lenert , Audrey R. Green , Ericka N. Merriwether , Michael D. Burton","doi":"10.1016/j.ynpai.2024.100169","DOIUrl":"10.1016/j.ynpai.2024.100169","url":null,"abstract":"<div><div>Fibromyalgia (FM) is a complex chronic musculoskeletal pain disorder with an elusive pathogenesis, with a strong implication of immune interactions. We recently found that IL-5 and the adaptive immune system mediates pain outcomes in fibromyalgia (FM) patients and preclinical models of FM-like chronic widespread pain (CWP). However, there is an active debate if FM/CWP has an autoimmune etiology. Preclinical models of CWP utilize a repeated insult paradigm, which resembles a primary, then secondary response similarly observed in the antibody response, in which the subsequent event causes a potentiated pain response. Recent translational studies have implicated immunoglobulins (Ig) and B-cells in FM/CWP pathophysiology. To understand if these are involved in preclinical models of CWP, we performed comprehensive B-cell phenotyping in the bone marrow, circulation, and popliteal (draining) lymph nodes in the two-hit acidic saline model of CWP. We found increased MHC class II-expressing B-cells in peripheral blood, increased activated plasma cells in peripheral blood, and increased memory B-cells in the bone marrow. Interestingly, acidic pH (4.0) injected mice have reduced levels of IgG1, independent of treatment with IL-5. We have demonstrated that the acidic saline model of CWP induces T-cell mediated activation of B-cells, increased active plasma cells, and increased memory B-cells in female mice.</div></div>","PeriodicalId":52177,"journal":{"name":"Neurobiology of Pain","volume":"16 ","pages":"Article 100169"},"PeriodicalIF":0.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142533681","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}
Recent evidence suggests that the descending modulatory pathways from the brainstem rostral ventromedial medulla (RVM) are important for bladder inflammatory pain. This study aimed to identify the long-term molecular changes in RVM neurons due to early life cystitis during neuronal development and the effect of reexposure later in adulthood. RVM tissues from two treatment protocols were used: (1) neonatal zymosan exposures with acute adult rechallenge (RC) and (2) only neonatal zymosan exposures (NRC). RNAseq analysis showed upregulation of several genes associated with synaptic plasticity (Grin1, Grip2, Notch1, Arc, and Scn2b) in the cystitis groups compared to controls in both protocols. The RC protocol exhibited a stronger treatment effect with significantly higher fold differences between the groups compared to the NRC protocol (p < 0.001, fold differences RC vs NRC). In microarrays, miR-34a-5p showed cystitis-induced downregulation in both protocols. Bioinformatics analysis identified multiple 3′UTRs complementary binding sites for miR-34a-5p on Grin2b, Notch1, Grip2, Scn2b, and Arc genes. The enhanced response in the RC protocol indicates a possible priming effect of early life cystitis on rechallenge in adulthood. These long-term molecular alterations may play a critical role in the development of chronic bladder pain conditions as seen in patients with Interstitial Cystitis/Bladder pain syndrome.
{"title":"Adult zymosan re-exposure exacerbates the molecular alterations in the brainstem rostral ventromedial medulla of rats with early life zymosan-induced cystitis","authors":"Bhavana Talluri , Sankar Addya , Maia Terashvili , Bidyut K Medda , Anjishnu Banerjee , Reza Shaker , Jyoti N Sengupta , Banani Banerjee","doi":"10.1016/j.ynpai.2024.100160","DOIUrl":"10.1016/j.ynpai.2024.100160","url":null,"abstract":"<div><p>Recent evidence suggests that the descending modulatory pathways from the brainstem rostral ventromedial medulla (RVM) are important for bladder inflammatory pain. This study aimed to identify the long-term molecular changes in RVM neurons due to early life cystitis during neuronal development and the effect of reexposure later in adulthood. RVM tissues from two treatment protocols were used: (1) neonatal zymosan exposures with acute adult rechallenge (RC) and (2) only neonatal zymosan exposures (NRC). RNAseq analysis showed upregulation of several genes associated with synaptic plasticity (Grin1, Grip2, Notch1, Arc, and Scn2b) in the cystitis groups compared to controls in both protocols. The RC protocol exhibited a stronger treatment effect with significantly higher fold differences between the groups compared to the NRC protocol (<em>p</em> < 0.001, fold differences RC vs NRC). In microarrays, miR-34a-5p showed cystitis-induced downregulation in both protocols. Bioinformatics analysis identified multiple 3′UTRs complementary binding sites for miR-34a-5p on Grin2b, Notch1, Grip2, Scn2b, and Arc genes. The enhanced response in the RC protocol indicates a possible priming effect of early life cystitis on rechallenge in adulthood. These long-term molecular alterations may play a critical role in the development of chronic bladder pain conditions as seen in patients with Interstitial Cystitis/Bladder pain syndrome.</p></div>","PeriodicalId":52177,"journal":{"name":"Neurobiology of Pain","volume":"16 ","pages":"Article 100160"},"PeriodicalIF":0.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2452073X24000114/pdfft?md5=031db0399b5e12d370342174b15ac83d&pid=1-s2.0-S2452073X24000114-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141784322","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}
Pub Date : 2024-07-01DOI: 10.1016/j.ynpai.2024.100165
Clem Gunter , Cody L. Jiang , Shae O. Zeimantz , Deborah M. Hegarty , Catherine W. Morgans , Tally M. Largent-Milnes , Sue A. Aicher
Photorefractive keratectomy (PRK) is a type of eye surgery that involves removal of the corneal epithelium and its associated nerves, which causes intense acute pain in most people. We used a rat model of corneal epithelium removal (corneal abrasion) to examine underlying cellular and molecular mechanisms. In this study, we used immunohistochemistry of trigeminal ganglion (TG) to assess neuronal content of CGRP and ATF3, as well as orbital tightening (OT) to assess spontaneous pain behaviors. CGRP is an important neuropeptide in pain modulation and ATF3 is often used as a nerve injury marker. We found dynamic changes in CGRP and ATF3 in TG; both increased significantly at 24 h following corneal abrasion and females had a more pronounced increase at 24 h compared to males. Interestingly, there was no sex difference in OT behaviors. Additionally, the number of cells containing either CGRP or ATF3 in each animal correlate significantly with their OT behavior at the assessed timepoint. Since CGRP increased most in females, we tested the effectiveness of Olcegepant, a CGRP antagonist, at reducing OT behaviors following corneal abrasion in female rats. Olcegepant (1 mg/kg) was given prior to and again at 24 h after abrasion but did not change OT behaviors at any time over a 1-week period. Examination of CGRP and ATF3 together in TG showed that they rarely colocalized, indicating that the cells with upregulated CGRP are distinct from those responding to epithelial nerve injury. The studies also show that underlying molecular responses may be sex specific.
{"title":"Activating transcription factor 3 (ATF3) and calcitonin gene-related peptide (CGRP) increase in trigeminal ganglion neurons in female rats after photorefractive keratectomy (PRK)-like corneal abrasion","authors":"Clem Gunter , Cody L. Jiang , Shae O. Zeimantz , Deborah M. Hegarty , Catherine W. Morgans , Tally M. Largent-Milnes , Sue A. Aicher","doi":"10.1016/j.ynpai.2024.100165","DOIUrl":"10.1016/j.ynpai.2024.100165","url":null,"abstract":"<div><p>Photorefractive keratectomy (PRK) is a type of eye surgery that involves removal of the corneal epithelium and its associated nerves, which causes intense acute pain in most people. We used a rat model of corneal epithelium removal (corneal abrasion) to examine underlying cellular and molecular mechanisms. In this study, we used immunohistochemistry of trigeminal ganglion (TG) to assess neuronal content of CGRP and ATF3, as well as orbital tightening (OT) to assess spontaneous pain behaviors. CGRP is an important neuropeptide in pain modulation and ATF3 is often used as a nerve injury marker. We found dynamic changes in CGRP and ATF3 in TG; both increased significantly at 24 h following corneal abrasion and females had a more pronounced increase at 24 h compared to males. Interestingly, there was no sex difference in OT behaviors. Additionally, the number of cells containing either CGRP or ATF3 in each animal correlate significantly with their OT behavior at the assessed timepoint. Since CGRP increased most in females, we tested the effectiveness of Olcegepant, a CGRP antagonist, at reducing OT behaviors following corneal abrasion in female rats. Olcegepant (1 mg/kg) was given prior to and again at 24 h after abrasion but did not change OT behaviors at any time over a 1-week period. Examination of CGRP and ATF3 together in TG showed that they rarely colocalized, indicating that the cells with upregulated CGRP are distinct from those responding to epithelial nerve injury. The studies also show that underlying molecular responses may be sex specific.</p></div>","PeriodicalId":52177,"journal":{"name":"Neurobiology of Pain","volume":"16 ","pages":"Article 100165"},"PeriodicalIF":0.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2452073X24000163/pdfft?md5=bf07ea2d331449286df30ec20031a4a3&pid=1-s2.0-S2452073X24000163-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142232497","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}
Pub Date : 2024-07-01DOI: 10.1016/j.ynpai.2024.100168
Federico Iseppon , Alexandros H. Kanellopoulos , Naxi Tian , Jun Zhou , Gozde Caan , Riccardo Chiozzi , Konstantinos Thalassinos , Cankut Çubuk , Myles J. Lewis , James J. Cox , Jing Zhao , Christopher G. Woods , John N. Wood
Genetic deletion and pharmacological inhibition are distinct approaches to unravelling pain mechanisms, identifying targets and developing new analgesics. Both approaches have been applied to the voltage-gated sodium channels Nav1.7 and Nav1.8. Genetic deletion of Nav1.8 in mice leads to a loss of pain and antagonists are effective analgesics. The situation with Nav1.7 is more complex. Complete embryonic loss of Nav1.7 in humans or in mouse sensory neurons leads to anosmia as well as profound analgesia as a result of diminished neurotransmitter release. This is mediated by enhanced endogenous opioid signaling in humans and mice. In contrast, anosmia is opioid-independent. Sensory neuron excitability and autonomic function appear to be normal.
Adult deletion of Nav1.7 in sensory neurons also leads to analgesia, but through diminished sensory and autonomic neuron excitability. There is no opioid component of analgesia or anosmia as shown by a lack of effect of naloxone. Pharmacological inhibition of Nav1.7 in mice and humans leads both to analgesia and dramatic side-effects on the autonomic nervous system with no therapeutic window. These data demonstrate that specific Nav1.7 channel blockers will fail as analgesic drugs. The viability of embryonic null mutants suggests that there are compensatory changes to replace the lost Nav1.7 channel. Here we show that sensory neuron sodium channels Nav1.1, Nav1.2 and β4 subunits detected by Mass Spectrometry are upregulated in Nav1.7 embryonic null neurons and, together with other proteome changes, potentially compensate for the loss of Nav1.7. Interestingly, many of the upregulated proteins are known to interact with Nav1.7.
{"title":"Sodium channels Nav1.7, Nav1.8 and pain; two distinct mechanisms for Nav1.7 null analgesia","authors":"Federico Iseppon , Alexandros H. Kanellopoulos , Naxi Tian , Jun Zhou , Gozde Caan , Riccardo Chiozzi , Konstantinos Thalassinos , Cankut Çubuk , Myles J. Lewis , James J. Cox , Jing Zhao , Christopher G. Woods , John N. Wood","doi":"10.1016/j.ynpai.2024.100168","DOIUrl":"10.1016/j.ynpai.2024.100168","url":null,"abstract":"<div><div>Genetic deletion and pharmacological inhibition are distinct approaches to unravelling pain mechanisms, identifying targets and developing new analgesics. Both approaches have been applied to the voltage-gated sodium channels Na<sub>v</sub>1.7 and Na<sub>v</sub>1.8. Genetic deletion of Na<sub>v</sub>1.8 in mice leads to a loss of pain and antagonists are effective analgesics. The situation with Nav1.7 is more complex. Complete embryonic loss of Na<sub>v</sub>1.7 in humans or in mouse sensory neurons leads to anosmia as well as profound analgesia as a result of diminished neurotransmitter release. This is mediated by enhanced endogenous opioid signaling in humans and mice. In contrast, anosmia is opioid-independent. Sensory neuron excitability and autonomic function appear to be normal.</div><div>Adult deletion of Na<sub>v</sub>1.7 in sensory neurons also leads to analgesia, but through diminished sensory and autonomic neuron excitability. There is no opioid component of analgesia or anosmia as shown by a lack of effect of naloxone. Pharmacological inhibition of Na<sub>v</sub>1.7 in mice and humans leads both to analgesia and dramatic side-effects on the autonomic nervous system with no therapeutic window. These data demonstrate that specific Na<sub>v</sub>1.7 channel blockers will fail as analgesic drugs. The viability of embryonic null mutants suggests that there are compensatory changes to replace the lost Na<sub>v</sub>1.7 channel. Here we show that sensory neuron sodium channels Na<sub>v</sub>1.1, Na<sub>v</sub>1.2 and β4 subunits detected by Mass Spectrometry are upregulated in Na<sub>v</sub>1.7 embryonic null neurons and, together with other proteome changes, potentially compensate for the loss of Na<sub>v</sub>1.7. Interestingly, many of the upregulated proteins are known to interact with Nav1.7.</div></div>","PeriodicalId":52177,"journal":{"name":"Neurobiology of Pain","volume":"16 ","pages":"Article 100168"},"PeriodicalIF":0.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142592629","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}
Pub Date : 2024-07-01DOI: 10.1016/j.ynpai.2024.100163
Yenisel Cruz-Almeida , Bella Mehta , Nele A. Haelterman , Alisa J. Johnson , Chloe Heiting , Malin Ernberg , Dana Orange , Martin Lotz , Jacqueline Boccanfuso , Shad B. Smith , Marlena Pela , Jyl Boline , Miguel Otero , Kyle Allen , Daniel Perez , Christopher Donnelly , Alejandro Almarza , Merissa Olmer , Henah Balkhi , Joost Wagenaar , Maryann Martone
<div><h3>Background</h3><p>The Restoring Joint Health and Function to Reduce Pain (RE-JOIN) Consortium is part of the Helping to End Addiction Long-term® (HEAL) Initiative. HEAL is an ambitious, NIH-wide initiative to speed scientific solutions to stem the national opioid public health crisis. The RE-JOIN consortium’s over-arching goal is to define how chronic joint pain-mediating neurons innervate different articular and <em>peri</em>-articular tissues, with a focus on the knee and temporomandibular joints (TMJ) across species employing the latest neuroscience approaches. The aim of this manuscript is to elucidate the human data gathered by the RE-JOIN consortium, as well as to expound upon its underlying rationale and the methodologies and protocols for harmonization and standardization that have been instituted by the RE-JOIN Consortium.</p></div><div><h3>Methods</h3><p>The consortium-wide human models working subgroup established the RE-JOIN minimal harmonized data elements that will be collected across all human studies and set the stage to develop parallel pre-clinical data collection standards. Data harmonization considerations included requirements from the HEAL program and recommendations from the consortium’s researchers and experts on informatics, knowledge management, and data curation.</p></div><div><h3>Results</h3><p>Multidisciplinary experts − including preclinical and clinical researchers, with both clinician-scientists- developed the RE-JOIN’s Minimal Human Data Standard with required domains and outcome measures to be collected across projects and institutions. The RE-JOIN minimal data standard will include HEAL Common Data Elements (CDEs) (e.g., standardized demographics, general pain, psychosocial and functional measures), and RE-JOIN common data elements (R-CDE) (i.e., both general and joint-specific standardized and clinically important self-reported pain and function measures, as well as pressure pain thresholds part of quantitative sensory testing). In addition, discretionary, site-specific measures will be collected by individual institutions (e.g., expanded quantitative sensory testing and gait biomechanical assessments), specific to the knee or TMJ. Research teams will submit datasets of standardized metadata to the RE-JOIN Data Coordinating Center (DCG) via a secure cloud-based central data repository and computing infrastructure for researchers to share and conduct analyses on data collected by or acquired for RE-JOIN. RE-JOIN datasets will have protected health information (PHI) removed and be publicly available on the SPARC portal and accessible through the HEAL Data Ecosystem.</p></div><div><h3>Conclusion</h3><p>Data Harmonization efforts provide the multidisciplinary consortium with an opportunity to effectively collaborate across decentralized research teams, and data standardization sets the framework for efficient future analyses of RE-JOIN data collected by the consortium. The harmonized phenotypic information
{"title":"Clinical and biobehavioral phenotypic assessments and data harmonization for the RE-JOIN research consortium: Recommendations for common data element selection","authors":"Yenisel Cruz-Almeida , Bella Mehta , Nele A. Haelterman , Alisa J. Johnson , Chloe Heiting , Malin Ernberg , Dana Orange , Martin Lotz , Jacqueline Boccanfuso , Shad B. Smith , Marlena Pela , Jyl Boline , Miguel Otero , Kyle Allen , Daniel Perez , Christopher Donnelly , Alejandro Almarza , Merissa Olmer , Henah Balkhi , Joost Wagenaar , Maryann Martone","doi":"10.1016/j.ynpai.2024.100163","DOIUrl":"10.1016/j.ynpai.2024.100163","url":null,"abstract":"<div><h3>Background</h3><p>The Restoring Joint Health and Function to Reduce Pain (RE-JOIN) Consortium is part of the Helping to End Addiction Long-term® (HEAL) Initiative. HEAL is an ambitious, NIH-wide initiative to speed scientific solutions to stem the national opioid public health crisis. The RE-JOIN consortium’s over-arching goal is to define how chronic joint pain-mediating neurons innervate different articular and <em>peri</em>-articular tissues, with a focus on the knee and temporomandibular joints (TMJ) across species employing the latest neuroscience approaches. The aim of this manuscript is to elucidate the human data gathered by the RE-JOIN consortium, as well as to expound upon its underlying rationale and the methodologies and protocols for harmonization and standardization that have been instituted by the RE-JOIN Consortium.</p></div><div><h3>Methods</h3><p>The consortium-wide human models working subgroup established the RE-JOIN minimal harmonized data elements that will be collected across all human studies and set the stage to develop parallel pre-clinical data collection standards. Data harmonization considerations included requirements from the HEAL program and recommendations from the consortium’s researchers and experts on informatics, knowledge management, and data curation.</p></div><div><h3>Results</h3><p>Multidisciplinary experts − including preclinical and clinical researchers, with both clinician-scientists- developed the RE-JOIN’s Minimal Human Data Standard with required domains and outcome measures to be collected across projects and institutions. The RE-JOIN minimal data standard will include HEAL Common Data Elements (CDEs) (e.g., standardized demographics, general pain, psychosocial and functional measures), and RE-JOIN common data elements (R-CDE) (i.e., both general and joint-specific standardized and clinically important self-reported pain and function measures, as well as pressure pain thresholds part of quantitative sensory testing). In addition, discretionary, site-specific measures will be collected by individual institutions (e.g., expanded quantitative sensory testing and gait biomechanical assessments), specific to the knee or TMJ. Research teams will submit datasets of standardized metadata to the RE-JOIN Data Coordinating Center (DCG) via a secure cloud-based central data repository and computing infrastructure for researchers to share and conduct analyses on data collected by or acquired for RE-JOIN. RE-JOIN datasets will have protected health information (PHI) removed and be publicly available on the SPARC portal and accessible through the HEAL Data Ecosystem.</p></div><div><h3>Conclusion</h3><p>Data Harmonization efforts provide the multidisciplinary consortium with an opportunity to effectively collaborate across decentralized research teams, and data standardization sets the framework for efficient future analyses of RE-JOIN data collected by the consortium. The harmonized phenotypic information","PeriodicalId":52177,"journal":{"name":"Neurobiology of Pain","volume":"16 ","pages":"Article 100163"},"PeriodicalIF":0.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2452073X2400014X/pdfft?md5=d0191c1c3bd2ea8857132f5af2a7e280&pid=1-s2.0-S2452073X2400014X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142087283","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}
Pub Date : 2024-07-01DOI: 10.1016/j.ynpai.2024.100171
Adam J. Dourson , Rachel S. Darken , Thomas J. Baranski , Robert W. Gereau 4th , Whitney Trotter Ross , Hadas Nahman-Averbuch
Migraine affects ∼12 % of the worldwide population and is more prevalent in females, which suggests a role of sex hormones in migraine pathophysiology. Most studies have focused on estrogen and progesterone, and the involvement of androgens has been less studied. However, due to the recent advances in androgen interventions, which could advance new androgen-based migraine treatments, it is critical to better understand the role of androgens in migraine. Testosterone, the most studied androgen, was found to have an antinociceptive effect in various animal and human pain studies. Thus, it could also have a protective effect related to lower migraine severity and prevalence. In this review, we discuss studies examining the role of androgens on migraine-related symptoms in migraine animal models. Additionally, we summarize the results of human studies comparing androgen levels between patients with migraine and healthy controls, studies assessing the relationships between androgen levels and migraine severity, and intervention studies examining the impact of testosterone treatment on migraine severity. Many of the studies have limitations, however, the results suggest that androgens may have a minor effect on migraine. Still, it is possible that androgens are involved in migraine pathophysiology in a sub-group of patients such as in adolescents or postmenopausal women. We discuss potential mechanisms in which testosterone, as the main androgen tested, can impact migraine. These mechanisms range from the cellular level to systems and behavior and include the effect of testosterone on sensory neurons, the immune and vascular systems, the stress response, brain function, and mood. Lastly, we suggest future directions to advance this line of research.
{"title":"The role of androgens in migraine pathophysiology","authors":"Adam J. Dourson , Rachel S. Darken , Thomas J. Baranski , Robert W. Gereau 4th , Whitney Trotter Ross , Hadas Nahman-Averbuch","doi":"10.1016/j.ynpai.2024.100171","DOIUrl":"10.1016/j.ynpai.2024.100171","url":null,"abstract":"<div><div>Migraine affects ∼12 % of the worldwide population and is more prevalent in females, which suggests a role of sex hormones in migraine pathophysiology. Most studies have focused on estrogen and progesterone, and the involvement of androgens has been less studied. However, due to the recent advances in androgen interventions, which could advance new androgen-based migraine treatments, it is critical to better understand the role of androgens in migraine. Testosterone, the most studied androgen, was found to have an antinociceptive effect in various animal and human pain studies. Thus, it could also have a protective effect related to lower migraine severity and prevalence. In this review, we discuss studies examining the role of androgens on migraine-related symptoms in migraine animal models. Additionally, we summarize the results of human studies comparing androgen levels between patients with migraine and healthy controls, studies assessing the relationships between androgen levels and migraine severity, and intervention studies examining the impact of testosterone treatment on migraine severity. Many of the studies have limitations, however, the results suggest that androgens may have a minor effect on migraine. Still, it is possible that androgens are involved in migraine pathophysiology in a sub-group of patients such as in adolescents or postmenopausal women. We discuss potential mechanisms in which testosterone, as the main androgen tested, can impact migraine. These mechanisms range from the cellular level to systems and behavior and include the effect of testosterone on sensory neurons, the immune and vascular systems, the stress response, brain function, and mood. Lastly, we suggest future directions to advance this line of research.</div></div>","PeriodicalId":52177,"journal":{"name":"Neurobiology of Pain","volume":"16 ","pages":"Article 100171"},"PeriodicalIF":0.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142533683","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}
Pub Date : 2024-07-01DOI: 10.1016/j.ynpai.2024.100173
Lara W. Crock , Rachel Rodgers , Nolan A. Huck , Lawrence A. Schriefer , Dylan Lawrence , Leran Wang , Gabriella P.B. Muwanga , Vivianne L. Tawfik , Megan T. Baldridge
Objective
This study aimed to evaluate pain metrics and gut microbiota differences from human subjects with complex regional pain syndrome (CRPS) compared to cohabitants (HHC) and non-cohabitating (biobank) controls. In addition, we aimed evaluate longitudinal changes of gut microbiota using a mouse model of acute and chronic CRPS.
Methods
In an observational, cross-sectional study, 25 patients with CRPS and 24 household controls (HHC) were recruited, completed pain questionnaires, and submitted stool samples. 23 biobank stool samples were matched to the CRPS group. Additionally, longitudinal stool samples were collected from a mouse model of acute and chronic CRPS. 16S rRNA gene sequencing analysis was performed on all samples.
Results
A diagnosis of CRPS is associated with higher pain, increased pain interference, and decreased physical and social function when compared to HHC. Interestingly, 46% of HHC reported significant daily pain. In the households where HHC were also suffering from pain, there was decreased bacterial richness and diversity when compared to households wherein only the participant with CRPS suffered from pain. Furthermore, when comparing households where the HHC had significant pain, CRPS was clinically more severe. In the mouse model of CRPS, we observed decreased bacterial richness and diversity when compared to non-cohabitating littermate controls.
Conclusions
Both humans living in chronic pain households and mice shared distinct taxa over the time course of disease and pain chronicity. These findings suggest that microbiota changes seen in CRPS as well as in a mouse model of CRPS may reflect pain chronicity and may indicate that pain alone can contribute to microbiota dysbiosis. The trial was registered at ClinicalTrials.gov (NCT03612193).
{"title":"Chronic pain and complex regional pain syndrome are associated with alterations to the intestinal microbiota in both humans and mice. An observational cross-sectional study","authors":"Lara W. Crock , Rachel Rodgers , Nolan A. Huck , Lawrence A. Schriefer , Dylan Lawrence , Leran Wang , Gabriella P.B. Muwanga , Vivianne L. Tawfik , Megan T. Baldridge","doi":"10.1016/j.ynpai.2024.100173","DOIUrl":"10.1016/j.ynpai.2024.100173","url":null,"abstract":"<div><h3>Objective</h3><div>This study aimed to evaluate pain metrics and gut microbiota differences from human subjects with complex regional pain syndrome (CRPS) compared to cohabitants (HHC) and non-cohabitating (biobank) controls. In addition, we aimed evaluate longitudinal changes of gut microbiota using a mouse model of acute and chronic CRPS.</div></div><div><h3>Methods</h3><div>In an observational, cross-sectional study, 25 patients with CRPS and 24 household controls (HHC) were recruited, completed pain questionnaires, and submitted stool samples. 23 biobank stool samples were matched to the CRPS group. Additionally, longitudinal stool samples were collected from a mouse model of acute and chronic CRPS. 16S rRNA gene sequencing analysis was performed on all samples.</div></div><div><h3>Results</h3><div>A diagnosis of CRPS is associated with higher pain, increased pain interference, and decreased physical and social function when compared to HHC. Interestingly, 46% of HHC reported significant daily pain. In the households where HHC were also suffering from pain, there was decreased bacterial richness and diversity when compared to households wherein only the participant with CRPS suffered from pain. Furthermore, when comparing households where the HHC had significant pain, CRPS was clinically more severe. In the mouse model of CRPS, we observed decreased bacterial richness and diversity when compared to non-cohabitating littermate controls.</div></div><div><h3>Conclusions</h3><div>Both humans living in chronic pain households and mice shared distinct taxa over the time course of disease and pain chronicity. These findings suggest that microbiota changes seen in CRPS as well as in a mouse model of CRPS may reflect pain chronicity and may indicate that pain alone can contribute to microbiota dysbiosis. The trial was registered at <span><span>ClinicalTrials.gov</span><svg><path></path></svg></span> (NCT03612193).</div></div>","PeriodicalId":52177,"journal":{"name":"Neurobiology of Pain","volume":"16 ","pages":"Article 100173"},"PeriodicalIF":0.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142748808","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}
Pub Date : 2024-07-01DOI: 10.1016/j.ynpai.2024.100162
Mohammed Zacky Ariffin , Si Yun Ng , Hamzah Nadia , Darrel Koh , Natasha Loh , Naomi Michiko , Sanjay Khanna
The neurokinin-1 receptors (NK1Rs) in the forebrain medial septum (MS) region are localized exclusively on cholinergic neurons that partly project to the hippocampus and the cingulate cortex (Cg), regions implicated in nociception. In the present study, we explored the hypothesis that neurotransmission at septal NK1R and hippocampal cholinergic mechanisms mediate experimental neuropathic pain in the rodent chronic constriction injury model (CCI). Our investigations showed that intraseptal microinjection of substance P (SP) in rat evoked a peripheral hypersensitivity (PH)-like response in uninjured animals that was attenuated by systemic atropine sulphate, a muscarinic-cholinergic receptor antagonist. Conversely, pre-emptive destruction of septal cholinergic neurons attenuated the development of PH in the CCI model that also prevented the expression of cellular markers of nociception in the spinal cord and the forebrain. Likewise, anti-nociception was evoked on intraseptal microinjection of L-733,060, an antagonist at NK1Rs, and on bilateral or unilateral microinjection of the cholinergic receptor antagonists, atropine or mecamylamine, into the different regions of the dorsal hippocampus (dH) or on bilateral microinjection into the Cg. Interestingly, the effect of L-733,060 was accompanied with a widespread decreased in levels of CCI-induced nociceptive cellular markers in forebrain that was not secondary to behaviour, suggesting an active modulation of nociceptive processing by transmission at NK1R in the medial septum. The preceding suggest that the development and maintenance of neuropathic nociception is facilitated by septal NK1R-dH cholinergic mechanisms which co-ordinately affect nociceptive processing in the dH and the Cg. Additionally, the data points to a potential strategy for pain modulation that combines anticholinergics and anti-NKRs.
{"title":"Neurokinin1 − cholinergic receptor mechanisms in the medial Septum-Dorsal hippocampus axis mediates experimental neuropathic pain","authors":"Mohammed Zacky Ariffin , Si Yun Ng , Hamzah Nadia , Darrel Koh , Natasha Loh , Naomi Michiko , Sanjay Khanna","doi":"10.1016/j.ynpai.2024.100162","DOIUrl":"10.1016/j.ynpai.2024.100162","url":null,"abstract":"<div><p>The neurokinin-1 receptors (NK1Rs) in the forebrain medial septum (MS) region are localized exclusively on cholinergic neurons that partly project to the hippocampus and the cingulate cortex (Cg), regions implicated in nociception. In the present study, we explored the hypothesis that neurotransmission at septal NK1R and hippocampal cholinergic mechanisms mediate experimental neuropathic pain in the rodent chronic constriction injury model (CCI). Our investigations showed that intraseptal microinjection of substance P (SP) in rat evoked a peripheral hypersensitivity (PH)-like response in uninjured animals that was attenuated by systemic atropine sulphate, a muscarinic-cholinergic receptor antagonist. Conversely, pre-emptive destruction of septal cholinergic neurons attenuated the development of PH in the CCI model that also prevented the expression of cellular markers of nociception in the spinal cord and the forebrain. Likewise, anti-nociception was evoked on intraseptal microinjection of L-733,060, an antagonist at NK1Rs, and on bilateral or unilateral microinjection of the cholinergic receptor antagonists, atropine or mecamylamine, into the different regions of the dorsal hippocampus (dH) or on bilateral microinjection into the Cg. Interestingly, the effect of L-733,060 was accompanied with a widespread decreased in levels of CCI-induced nociceptive cellular markers in forebrain that was not secondary to behaviour, suggesting an active modulation of nociceptive processing by transmission at NK1R in the medial septum. The preceding suggest that the development and maintenance of neuropathic nociception is facilitated by septal NK1R-dH cholinergic mechanisms which co-ordinately affect nociceptive processing in the dH and the Cg. Additionally, the data points to a potential strategy for pain modulation that combines anticholinergics and anti-NKRs.</p></div>","PeriodicalId":52177,"journal":{"name":"Neurobiology of Pain","volume":"16 ","pages":"Article 100162"},"PeriodicalIF":0.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2452073X24000138/pdfft?md5=4e1189eff9a9e0852ab70166f995d0bc&pid=1-s2.0-S2452073X24000138-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141963572","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}
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