IF 5.9 1区医学

PAIN® Pub Date : 2024-10-01 Epub Date: 2024-05-24 DOI: 10.1097/j.pain.0000000000003245

Sara Coppi, Karin B Jensen, H Henrik Ehrsson

{"title":"Eliciting the rubber hand illusion by the activation of nociceptive C and Aδ fibers.","authors":"Sara Coppi, Karin B Jensen, H Henrik Ehrsson","doi":"10.1097/j.pain.0000000000003245","DOIUrl":"10.1097/j.pain.0000000000003245","url":null,"abstract":"Abstract: The coherent perceptual experience of one's own body depends on the processing and integration of signals from multiple sensory modalities, including vision, touch, and proprioception. Although nociception provides critical information about damage to the tissues of one's body, little is known about how nociception contributes to own-body perception. A classic experimental approach to investigate the perceptual and neural mechanisms involved in the multisensory experience of one's own body is the rubber hand illusion (RHI). During the RHI, people experience a rubber hand as part of their own body (sense of body ownership) caused by synchronized stroking of the rubber hand in the participant's view and the hidden participant's real hand. We examined whether the RHI can be elicited by visual and \"pure\" nociceptive stimulation, ie, without tactile costimulation, and if so, whether it follows the basic perceptual rules of the illusion. In 6 separate experiments involving a total of 180 healthy participants, we used a Nd:YAP laser stimulator to specifically target C and Aδ fibers in the skin and compared the illusion condition (congruent visuonociceptive stimulation) to control conditions of incongruent visuonociceptive, incongruent visuoproprioceptive, and no nociceptive stimulation. The illusion was quantified through direct (questionnaire) and indirect (proprioceptive drift) behavioral measures. We found that a nociceptive rubber hand illusion (N-RHI) could be elicited and that depended on the spatiotemporal congruence of visuonociceptive signals, consistent with basic principles of multisensory integration. Our results suggest that nociceptive information shapes multisensory bodily awareness and contributes to the sense of body ownership.","PeriodicalId":19921,"journal":{"name":"PAIN®","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11404332/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141093670","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The spinal cord, a computational system that generates the thermal grill illusion and other psychophysical phenomena. 脊髓是产生热烧烤幻觉和其他心理物理现象的计算系统。

IF 5.9 1区医学

PAIN® Pub Date : 2024-10-01 Epub Date: 2024-07-26 DOI: 10.1097/j.pain.0000000000003353

Marieke Niesters, Albert Dahan

引用次数: 0

Recent developments and challenges in positron emission tomography imaging of gliosis in chronic neuropathic pain. 慢性神经病理性疼痛神经胶质增生正电子发射断层成像的最新进展与挑战。

IF 5.9 1区医学

PAIN® Pub Date : 2024-10-01 Epub Date: 2024-05-07 DOI: 10.1097/j.pain.0000000000003247

Gaelle M Emvalomenos, James W M Kang, Bianca Jupp, Richelle Mychasiuk, Kevin A Keay, Luke A Henderson

{"title":"Recent developments and challenges in positron emission tomography imaging of gliosis in chronic neuropathic pain.","authors":"Gaelle M Emvalomenos, James W M Kang, Bianca Jupp, Richelle Mychasiuk, Kevin A Keay, Luke A Henderson","doi":"10.1097/j.pain.0000000000003247","DOIUrl":"10.1097/j.pain.0000000000003247","url":null,"abstract":"Abstract: Understanding the mechanisms that underpin the transition from acute to chronic pain is critical for the development of more effective and targeted treatments. There is growing interest in the contribution of glial cells to this process, with cross-sectional preclinical studies demonstrating specific changes in these cell types capturing targeted timepoints from the acute phase and the chronic phase. In vivo longitudinal assessment of the development and evolution of these changes in experimental animals and humans has presented a significant challenge. Recent technological advances in preclinical and clinical positron emission tomography, including the development of specific radiotracers for gliosis, offer great promise for the field. These advances now permit tracking of glial changes over time and provide the ability to relate these changes to pain-relevant symptomology, comorbid psychiatric conditions, and treatment outcomes at both a group and an individual level. In this article, we summarize evidence for gliosis in the transition from acute to chronic pain and provide an overview of the specific radiotracers available to measure this process, highlighting their potential, particularly when combined with ex vivo / in vitro techniques, to understand the pathophysiology of chronic neuropathic pain. These complementary investigations can be used to bridge the existing gap in the field concerning the contribution of gliosis to neuropathic pain and identify potential targets for interventions.","PeriodicalId":19921,"journal":{"name":"PAIN®","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140877036","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Disentangling the spinal mechanisms of illusory heat and burning sensations in the thermal grill illusion. 解析热烧烤幻觉中虚幻热感和灼烧感的脊髓机制。

IF 5.9 1区医学

PAIN® Pub Date : 2024-10-01 Epub Date: 2024-08-23 DOI: 10.1097/j.pain.0000000000003352

Alexandra G Mitchell, Jesper Fischer Ehmsen, Daniel Elmstrøm Christensen, Anna Villaume Stuckert, Patrick Haggard, Francesca Fardo

{"title":"Disentangling the spinal mechanisms of illusory heat and burning sensations in the thermal grill illusion.","authors":"Alexandra G Mitchell, Jesper Fischer Ehmsen, Daniel Elmstrøm Christensen, Anna Villaume Stuckert, Patrick Haggard, Francesca Fardo","doi":"10.1097/j.pain.0000000000003352","DOIUrl":"10.1097/j.pain.0000000000003352","url":null,"abstract":"Abstract: The thermal grill illusion (TGI), a phenomenon in which the juxtaposition of innocuous warm and cold temperatures on the skin elicits a burning sensation, offers a unique perspective to how pain occurs in response to harmless stimuli. We investigated the role of the spinal cord in the generation of the TGI across 2 experiments (total n = 80). We applied heat and cold stimuli to dermatomes, areas of skin innervated by a single spinal nerve, that mapped onto adjacent or nonadjacent spinal segments. Enhanced warm and burning ratings during the TGI were observed when cold and warm stimuli were confined within the same dermatome. Furthermore, we found the spatial organisation of warm and cold stimuli within and across dermatomes affected TGI perception. Perceived warmth and burning intensity increased when the cold stimulus projected to the segment more caudal to the warm stimulus, whereas perceived cold during the TGI decreased compared with the opposite spatial arrangement. This suggests that the perception of TGI is enhanced when cold afferents are projected to spinal segments positioned caudally in relation to those receiving warm afferents. Our results indicate distinct interaction of sensory pathways based on the segmental arrangement of afferent fibres and are consistent with current interpretations of the spread and integration of thermosensory information along the spinal cord.","PeriodicalId":19921,"journal":{"name":"PAIN®","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142056311","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Sex-dependent effects of the targeted NGF mutation (R100E) on pain behavior, joint inflammation, and bone erosion in mice. 靶向 NGF 突变（R100E）对小鼠疼痛行为、关节炎症和骨侵蚀的影响与性别有关。

IF 7.4 1区医学

PAIN® Pub Date : 2024-09-25 DOI: 10.1097/j.pain.0000000000003343

Carlos E Morado-Urbina,Jungo Kato,Katalin Sandor,Juan Antonio Vazquez-Mora,Kristina Ängeby Möller,Nils Simon,Jaira Salcido,Arisai Martinez-Martinez,Enriqueta Munoz-Islas,Juan Miguel Jimenez-Andrade,Camilla I Svensson

{"title":"Sex-dependent effects of the targeted NGF mutation (R100E) on pain behavior, joint inflammation, and bone erosion in mice.","authors":"Carlos E Morado-Urbina,Jungo Kato,Katalin Sandor,Juan Antonio Vazquez-Mora,Kristina Ängeby Möller,Nils Simon,Jaira Salcido,Arisai Martinez-Martinez,Enriqueta Munoz-Islas,Juan Miguel Jimenez-Andrade,Camilla I Svensson","doi":"10.1097/j.pain.0000000000003343","DOIUrl":"https://doi.org/10.1097/j.pain.0000000000003343","url":null,"abstract":"Nerve growth factor (NGF)-R100E is a mutated form of human recombinant NGF that reduces the binding of NGF to its p75NTR receptor while retaining its affinity toward the TrkA receptor. Here, we used human wild type NGF and NGF-R100E knock-in mice to investigate the effects of this NGF mutation on inflammation-induced pain-related behaviors and bone loss. The hNGF-R100E mutation did not alter the nerve fiber density in the sciatic nerve, ankle joint synovium, and skin of naïve mice. Withdrawal responses to mechanical, thermal, and cold stimuli before and after joint inflammation induced by intra-articular injection of complete Freund adjuvant (CFA) were similar between human recombinant nerve growth factor-wild type and hNGF-R100E male and female mice while weight bearing and gait analysis revealed significant differences. Intriguingly, hNGF-R100E male and female mice showed only mild changes, indicating lower degrees of deep joint-related pain compared to their wild type counterparts. Furthermore, micro-CT analysis demonstrated that hNGF-R100E female mice, but not males, were protected from CFA-induced bone loss, and mRNA analysis showed a different gene regulation indicating a sex-dependent relationship between NGF, inflammation, and bone loss. In conclusion, our study reveals that the hNGF-R100E mutation renders mice insensitive to inflammation-induced impact on joint loading and gait while preserving the development of the peripheral nociceptive neurons and sensitivity to punctate stimulation of the skin. Notably, the mutation uncovers a sex-dependent relationship between NGF and inflammation-induced bone loss. These findings offer valuable insights into NGF as a target for pain management and the interplay between NGF and bone architecture.","PeriodicalId":19921,"journal":{"name":"PAIN®","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142324921","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Decoding pain: uncovering the factors that affect the performance of neuroimaging-based pain models. 解码疼痛：揭示影响基于神经影像的疼痛模型性能的因素。

IF 7.4 1区医学

PAIN® Pub Date : 2024-09-25 DOI: 10.1097/j.pain.0000000000003392

Dong Hee Lee,Sungwoo Lee,Choong-Wan Woo

{"title":"Decoding pain: uncovering the factors that affect the performance of neuroimaging-based pain models.","authors":"Dong Hee Lee,Sungwoo Lee,Choong-Wan Woo","doi":"10.1097/j.pain.0000000000003392","DOIUrl":"https://doi.org/10.1097/j.pain.0000000000003392","url":null,"abstract":"Neuroimaging-based pain biomarkers, when combined with machine learning techniques, have demonstrated potential in decoding pain intensity and diagnosing clinical pain conditions. However, a systematic evaluation of how different modeling options affect model performance remains unexplored. This study presents the results from a comprehensive literature survey and benchmark analysis. We conducted a survey of 57 previously published articles that included neuroimaging-based predictive modeling of pain, comparing classification and prediction performance based on the following modeling variables-the levels of data, spatial scales, idiographic vs population models, and sample sizes. The findings revealed a preference for population-level modeling with brain-wide features, aligning with the goal of clinical translation of neuroimaging biomarkers. However, a systematic evaluation of the influence of different modeling options was hindered by a limited number of independent test results. This prompted us to conduct benchmark analyses using a locally collected functional magnetic resonance imaging dataset (N = 124) involving an experimental thermal pain task. The results demonstrated that data levels, spatial scales, and sample sizes significantly impact model performance. Specifically, incorporating more pain-related brain regions, increasing sample sizes, and averaging less data during training and more data during testing improved performance. These findings offer useful guidance for developing neuroimaging-based biomarkers, underscoring the importance of strategic selection of modeling approaches to build better-performing neuroimaging pain biomarkers. However, the generalizability of these findings to clinical pain requires further investigation.","PeriodicalId":19921,"journal":{"name":"PAIN®","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142324924","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Dual Kv7.2/3-TRPV1 modulators inhibit nociceptor hyperexcitability and alleviate pain without target-related side effects. 双重 Kv7.2/3-TRPV1 调节剂可抑制痛觉感受器过度兴奋并减轻疼痛，同时不会产生与靶点相关的副作用。

IF 7.4 1区医学

PAIN® Pub Date : 2024-09-24 DOI: 10.1097/j.pain.0000000000003390

Adi Raveh,Yefim Pen,Alon Silberman,Asher Peretz,Bernard Attali,Laura Maile,Steve Davidson,Alan D Brown,Jeffrey D Kennedy,Haim Belinson

{"title":"Dual Kv7.2/3-TRPV1 modulators inhibit nociceptor hyperexcitability and alleviate pain without target-related side effects.","authors":"Adi Raveh,Yefim Pen,Alon Silberman,Asher Peretz,Bernard Attali,Laura Maile,Steve Davidson,Alan D Brown,Jeffrey D Kennedy,Haim Belinson","doi":"10.1097/j.pain.0000000000003390","DOIUrl":"https://doi.org/10.1097/j.pain.0000000000003390","url":null,"abstract":"Persistent or chronic pain is the primary reason people seek medical care, yet current therapies are either limited in efficacy or cause intolerable side effects. Diverse mechanisms contribute to the basic phenomena of nociceptor hyperexcitability that initiates and maintains pain. Two prominent players in the modulation of nociceptor hyperexcitability are the transient receptor potential vanilloid type 1 (TRPV1) ligand-gated ion channel and the voltage-gated potassium channel, Kv7.2/3, that reciprocally regulate neuronal excitability. Across many drug development programs targeting either TRPV1 or Kv7.2/3, significant evidence has been accumulated to support these as highly relevant targets; however, side effects that are poorly separated from efficacy have limited the successful clinical translation of numerous Kv7.2/3 and TRPV1 drug development programs. We report here the pharmacological profile of 3 structurally related small molecule analogues that demonstrate a novel mechanism of action (MOA) of dual modulation of Kv7.2/3 and TRPV1. Specifically, these compounds simultaneously activate Kv7.2/3 and enable unexpected specific and potent inhibition of TRPV1. This in vitro potency translated to significant analgesia in vivo in several animal models of acute and chronic pain. Importantly, this specific MOA is not associated with any previously described Kv7.2/3 or TRPV1 class-specific side effects. We suggest that the therapeutic potential of this MOA is derived from the selective and specific targeting of a subpopulation of nociceptors found in rodents and humans. This efficacy and safety profile supports the advancement of dual TRPV1-Kv7.2/3 modulating compounds into preclinical and clinical development for the treatment of chronic pain.","PeriodicalId":19921,"journal":{"name":"PAIN®","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142324922","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The conotoxin Contulakin-G reverses hypersensitivity observed in rodent models of cancer-induced bone pain without inducing tolerance or motor disturbance. 在癌症诱发骨痛的啮齿类动物模型中，康妥毒素 Contulakin-G 可逆转观察到的超敏反应，而不会诱发耐受性或运动障碍。

IF 5.9 1区医学

PAIN® Pub Date : 2024-09-19 DOI: 10.1097/j.pain.0000000000003391

Laurent F Martin, Moyad Almuslim, Khaled A Ismail, Mohab M Ibrahim, Aubin Moutal, Kevin Cheng, Harrison J Stratton, Theodore J Price, Todd W Vanderah, Baldomero M Olivera, Rajesh Khanna, Amol Patwardhan

{"title":"The conotoxin Contulakin-G reverses hypersensitivity observed in rodent models of cancer-induced bone pain without inducing tolerance or motor disturbance.","authors":"Laurent F Martin, Moyad Almuslim, Khaled A Ismail, Mohab M Ibrahim, Aubin Moutal, Kevin Cheng, Harrison J Stratton, Theodore J Price, Todd W Vanderah, Baldomero M Olivera, Rajesh Khanna, Amol Patwardhan","doi":"10.1097/j.pain.0000000000003391","DOIUrl":"https://doi.org/10.1097/j.pain.0000000000003391","url":null,"abstract":"Abstract: As the incidence and survival rates of patients with cancer continues to grow, an increasing number of people are living with comorbidities, which often manifests as cancer-induced bone pain (CIBP). The majority of patients with CIBP report poor pain control from currently available analgesics. A conotoxin, Contulakin-G (CGX), has been demonstrated to be an antinociceptive agent in postsurgical and neuropathic pain states via a neurotensin receptor 2 (NTSR2)-mediated pathway. However, the efficacy and side effect profile of CGX have never been assessed in CIBP. Here, we evaluated CGX's antinociceptive potential in a rodent model of CIBP. We hypothesized that CGX engages the NTSR2 pathway, providing pain relief with minimal tolerance and motor side effects. Our results demonstrated that CGX intrathecal injection in mice with CIBP attenuated both spontaneous pain behaviors and evoked mechanical hypersensitivity, regardless of their sex. Furthermore, the antinociceptive effect of CGX was dependent upon expression of NTSR2 and the R-type voltage-gated calcium channel (Cav2.3); gene editing of these targets abolished CGX antinociception without affecting morphine antinociception. Examination of the side effect profile of CGX demonstrated that, unlike morphine, chronic intrathecal infusion maintained antinociception with reduced tolerance in rats with CIBP. Moreover, at antinociceptive doses, CGX had no impact on motor behavior in rodents with CIBP. Finally, RNAScope and immunoblotting analysis revealed expression of NTSR2 in both dorsal and ventral horns, while Cav2.3 was minimally expressed in the ventral horn, possibly explaining the sensory selectivity of CGX. Together, these findings support advancing CGX as a potential therapeutic for cancer pain.","PeriodicalId":19921,"journal":{"name":"PAIN®","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142293022","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Species-specific differences and the role of Nav1.9 in pain pathophysiology. 物种特异性差异和 Nav1.9 在疼痛病理生理学中的作用。

IF 5.9 1区医学

PAIN® Pub Date : 2024-09-19 DOI: 10.1097/j.pain.0000000000003395

Sulayman D Dib-Hajj, Stephen G Waxman

引用次数: 0

Persistent (Nav1.9) sodium currents in human dorsal root ganglion neurons. 人类背根神经节神经元中的持续（Nav1.9）钠电流。

IF 5.9 1区医学

PAIN® Pub Date : 2024-09-19 DOI: 10.1097/j.pain.0000000000003394

Xiulin Zhang, Jane E Hartung, Michael S Gold

{"title":"Persistent (Nav1.9) sodium currents in human dorsal root ganglion neurons.","authors":"Xiulin Zhang, Jane E Hartung, Michael S Gold","doi":"10.1097/j.pain.0000000000003394","DOIUrl":"https://doi.org/10.1097/j.pain.0000000000003394","url":null,"abstract":"Abstract: Nav1.9 is of interest to the pain community for a number of reasons, including the human mutations in the gene encoding Nav1.9, SCN11a, that are associated with both pain and loss of pain phenotypes. However, because much of what we know about the biophysical properties of Nav1.9 has been learned through the study of rodent sensory neurons, and there is only 76% identity between human and rodent homologs of SCN11a, there is reason to suggest that there may be differences in the biophysical properties of the channels in human and rodent sensory neurons, and consequently, the contribution of these channels to the control of sensory neuron excitability, if not pain. Thus, the purpose of this study was to characterize Nav1.9 currents in human sensory neurons and compare the properties of these currents with those in rat sensory neurons recorded under identical conditions. Whole-cell patch clamp techniques were used to record Nav1.9 currents in isolated sensory neurons in vitro. Our results indicate that several of the core biophysical properties of the currents, including persistence and a low threshold for activation, are conserved across species. However, we noted a number of potentially important differences between the currents in human and rat sensory neurons including a lower threshold for activation, higher threshold for inactivation, slower deactivation, and faster recovery from slow inactivation. Human Nav1.9 was inhibited by inflammatory mediators, whereas rat Nav1.9 was potentiated. Our results may have implications for the role of Nav1.9 in sensory, if not nociceptive signaling.","PeriodicalId":19921,"journal":{"name":"PAIN®","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142293018","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

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