Molecular Pain最新文献

{"title":"Mechanical and chemical itch regulated by neuropeptide Y-Y₁ signaling.","authors":"Sihan Chen, Junhui Chen, Dan Tang, Wen Yin, Saihong Xu, Po Gao, Yingfu Jiao, Weifeng Yu","doi":"10.1177/17448069241242982","DOIUrl":"10.1177/17448069241242982","url":null,"abstract":"<p><p>Itch is a somatosensory sensation to remove potential harmful stimulation with a scratching desire, which could be divided into mechanical and chemical itch according to diverse stimuli, such as wool fiber and insect biting. It has been reported that neuropeptide Y (NPY) neurons, a population of spinal inhibitory interneurons, could gate the transmission of mechanical itch, with no effect on chemical itch. In our study, we verified that chemogenetic activation of NPY neurons could inhibit the mechanical itch as well as the chemical itch, which also attenuated the alloknesis phenomenon in the chronic dry skin model. Afterwards, intrathecal administration of NPY1R agonist, [Leu³¹, Pro³⁴]-NPY (LP-NPY), showed the similar inhibition effect on mechanical itch, chemical itch and alloknesis as chemo-activation of NPY neurons. Whereas, intrathecal administration of NPY1R antagonist BIBO 3304 enhanced mechanical itch and reversed the alloknesis phenomenon inhibited by LP-NPY treatment. Moreover, selectively knocking down NPY1R by intrathecal injection of <i>Npy1r</i> siRNA enhanced mechanical and chemical itch behavior as well. These results indicate that NPY neurons in spinal cord regulate mechanical and chemical itch, and alloknesis in dry skin model through NPY1 receptors.</p>","PeriodicalId":19010,"journal":{"name":"Molecular Pain","volume":" ","pages":"17448069241242982"},"PeriodicalIF":3.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10981256/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140132079","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of inflammation on the properties of Nav1.8-ChR2-positive and Nav1.8-ChR2-negative afferent mechanoreceptors in the hindpaw glabrous skin of mice.","authors":"Akihiro Yamada, Ayaka Yamada, Jennifer Ling, Hidemasa Furue, Jianguo G Gu","doi":"10.1177/17448069241240452","DOIUrl":"10.1177/17448069241240452","url":null,"abstract":"<p><p>We recently used Nav1.8-ChR2 mice in which Nav1.8-expressing afferents were optogenetically tagged to classify mechanosensitive afferents into Nav1.8-ChR2-positive and Nav1.8-ChR2-negative mechanoreceptors. We found that the former were mainly high threshold mechanoreceptors (HTMRs), while the latter were low threshold mechanoreceptors (LTMRs). In the present study, we further investigated whether the properties of these mechanoreceptors were altered following tissue inflammation. Nav1.8-ChR2 mice received a subcutaneous injection of saline or Complete Freund's Adjuvant (CFA) in the hindpaws. Using the hind paw glabrous skin-tibial nerve preparation and the pressure-clamped single-fiber recordings, we found that CFA-induced hind paw inflammation lowered the mechanical threshold of many Nav1.8-ChR2-positive Aβ-fiber mechanoreceptors but heightened the mechanical threshold of many Nav1.8-ChR2-negative Aβ-fiber mechanoreceptors. Spontaneous action potential impulses were not observed in Nav1.8-ChR2-positive Aβ-fiber mechanoreceptors but occurred in Nav1.8-ChR2-negative Aβ-fiber mechanoreceptors with a lower mechanical threshold in the saline goup, and a higher mechanical threshold in the CFA group. No significant change was observed in the mechanical sensitivity of Nav1.8-ChR2-positive and Nav1.8-ChR2-negative Aδ-fiber mechanoreceptors and Nav1.8-ChR2-positive C-fiber mechanoreceptors following hind paw inflammation. Collectively, inflammation significantly altered the functional properties of both Nav1.8-ChR2-positive and Nav1.8-ChR2-negative Aβ-fiber mechanoreceptors, which may contribute to mechanical allodynia during inflammation.</p>","PeriodicalId":19010,"journal":{"name":"Molecular Pain","volume":" ","pages":"17448069241240452"},"PeriodicalIF":3.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10960352/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140028451","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of calcium-stimulated adenylyl cyclase subtype 1 (AC1) for the treatment of pain and anxiety symptoms in Parkinson's disease mice model.","authors":"Zhaoxiang Zhou, Qi-Yu Chen, Min Zhuo, Ping-Yi Xu","doi":"10.1177/17448069241266683","DOIUrl":"10.1177/17448069241266683","url":null,"abstract":"<p><p>Pain and anxiety are two common and undertreated non-motor symptoms in Parkinson's disease (PD), which affect the life quality of PD patients, and the underlying mechanisms remain unclear. As an important subtype of adenylyl cyclases (ACs), adenylyl cyclase subtype 1 (AC1) is critical for the induction of cortical long-term potentiation (LTP) and injury induced synaptic potentiation in the cortical areas including anterior cingulate cortex (ACC) and insular cortex (IC). Genetic deletion of AC1 or pharmacological inhibition of AC1 improved chronic pain and anxiety in different animal models. In this study, we proved the motor deficit, pain and anxiety symptoms of PD in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice model. As a lead candidate AC1 inhibitor, oral administration (1 dose and seven doses) of NB001 (20 and 40 mg/kg) showed significant analgesic effect in MPTP-treated mice, and the anxiety behavior was also reduced (40 mg/kg). By using genetic knockout mice, we found that AC1 knockout mice showed reduced pain and anxiety symptoms after MPTP administration, but not AC8 knockout mice. In summary, genetic deletion of AC1 or pharmacological inhibition of AC1 improved pain and anxiety symptoms in PD model mice, but didn't affect motor function. These results suggest that NB001 is a potential drug for the treatment of pain and anxiety symptoms in PD patients by inhibiting AC1 target.</p>","PeriodicalId":19010,"journal":{"name":"Molecular Pain","volume":" ","pages":"17448069241266683"},"PeriodicalIF":2.8,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11282525/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141443091","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Altered intra- and inter-network functional activity among migraine, chronic migraine, and trigeminal neuralgia.","authors":"Qichen Zhou, Rong Zhao, Zhaoxia Qin, Yapeng Qi, Wenshuang Tang, Lan Liu, Weikan Wang, Jian-Ren Liu, Xiaoxia Du","doi":"10.1177/17448069241300939","DOIUrl":"10.1177/17448069241300939","url":null,"abstract":"<p><strong>Objective: </strong>This study aimed to investigate the specific manifestations and differences in brain network activity and functional connectivity between brain networks in patients with trigeminal neuralgia and migraine, aiming to reveal the neural basis of these two diseases.</p><p><strong>Background: </strong>Head and facial pain, including trigeminal neuralgia and migraine, is prevalent globally. However, the underlying neural mechanisms of these conditions remain unclear. Resting-state functional connectivity studies based on independent component analysis (ICA) may offer new insights into these diseases.</p><p><strong>Methods: </strong>The study involved 23 chronic migraine, 37 episodic migraine, 21 trigeminal neuralgia patients, and 33 age- and gender-matched controls. Resting-state functional magnetic resonance imaging was performed, and five sets of brain network components were extracted through ICA. Neuronal activity indicators were calculated for each participant's independent components, including amplitudes of low-frequency fluctuation (ALFF) and regional homogeneity (ReHo). Functional connectivity was also assessed and compared among the four groups.</p><p><strong>Results: </strong>Trigeminal neuralgia patients showed reduced ALFF in the dorsal attention network versus episodic migraine patients and controls. Both trigeminal neuralgia and chronic migraine patients had decreased ReHo in this network. Migraine patients had weaker connectivity between the default mode and visual networks than controls. Trigeminal neuralgia patients also showed higher connectivity between the somatosensory motor and dorsal attention networks. Compared to episodic migraine, trigeminal neuralgia, and chronic migraine patients had increased connectivity between the visual and dorsal attention networks.</p><p><strong>Conclusion: </strong>The study provides evidence that long-term chronic head and facial pain may contribute to abnormalities in the activation and connectivity of the dorsal attention network. Compared to migraine patients, trigeminal neuralgia patients exhibit abnormal brain network connectivity, particularly within the somatomotor network, which may explain the presence of significant \"trigger points.\" These findings offer new perspectives for understanding the characteristics of different head and facial pain subtypes.</p>","PeriodicalId":19010,"journal":{"name":"Molecular Pain","volume":"20 ","pages":"17448069241300939"},"PeriodicalIF":2.8,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11629411/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142801719","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Understanding the kynurenine pathway: A narrative review on its impact across chronic pain conditions.","authors":"Ebrahim Hazrati, Seyed Parsa Eftekhar, Reza Mosaed, Saeed Shiralizadeh Dini, Mehrshad Namazi","doi":"10.1177/17448069241275097","DOIUrl":"10.1177/17448069241275097","url":null,"abstract":"<p><p>Chronic pain is a debilitating symptom with a significant negative impact on the quality of life and socioeconomic status, particularly among adults and the elderly. Major Depressive Disorder (MDD) stands out as one of the most important comorbid disorders accompanying chronic pain. The kynurenine pathway serves as the primary route for tryptophan degradation and holds critical significance in various biological processes, including the regulation of neurotransmitters, immune responses, cancer development, metabolism, and inflammation. This review encompasses key research studies related to the kynurenine pathway in the context of headache, neuropathic pain, gastrointestinal disorders, fibromyalgia, chronic fatigue syndrome, and MDD. Various metabolites produced in the kynurenine pathway, such as kynurenic acid and quinolinic acid, exhibit neuroprotective and neurotoxic effects, respectively. Recent studies have highlighted the significant involvement of kynurenine and its metabolites in the pathophysiology of pain. Moreover, pharmacological interventions targeting the regulation of the kynurenine pathway have shown therapeutic promise in pain management. Understanding the underlying mechanisms of this pathway presents an opportunity for developing personalized, innovative, and non-opioid approaches to pain treatment. Therefore, this narrative review explores the role of the kynurenine pathway in various chronic pain disorders and its association with depression and chronic pain.</p>","PeriodicalId":19010,"journal":{"name":"Molecular Pain","volume":" ","pages":"17448069241275097"},"PeriodicalIF":2.8,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11331475/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141879072","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advances in the pathological mechanisms and clinical treatments of chronic visceral pain.","authors":"Yong-Chang Li, Fu-Chao Zhang, Timothy W Xu, Rui-Xia Weng, Hong-Hong Zhang, Qian-Qian Chen, Shufen Hu, Rong Gao, Rui Li, Guang-Yin Xu","doi":"10.1177/17448069241305942","DOIUrl":"10.1177/17448069241305942","url":null,"abstract":"<p><p>Chronic visceral pain stems from internal organs and is frequently associated with functional gastrointestinal disorders, like irritable bowel syndrome (IBS). Since the underlying mechanisms of visceral pain remain largely unclear, clinical management is often limited and ineffective. Comprehensive research into the pathogenesis of visceral pain, along with the development of personalized therapeutic strategies, is crucial for advancing treatment options. Studies suggest that imbalances in purinergic receptors and neural circuit function are closely linked to the onset of visceral pain. In this review, we will explore the etiology and pathological mechanisms underlying visceral pain, with a focus on ion channels, epigenetic factors, and neural circuits, using functional gastrointestinal disorders as case studies. Finally, we will summarize and evaluate emerging treatments and potential initiatives aimed at managing visceral pain.</p>","PeriodicalId":19010,"journal":{"name":"Molecular Pain","volume":"20 ","pages":"17448069241305942"},"PeriodicalIF":2.8,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11645724/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142823912","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A note on estimating absolute cytosolic Ca²⁺ concentration in sensory neurons using a single wavelength Ca²⁺ indicator.","authors":"James P Higham, Ewan St John Smith, David C Bulmer","doi":"10.1177/17448069241230420","DOIUrl":"10.1177/17448069241230420","url":null,"abstract":"<p><p>Ca²⁺ imaging is frequently used in the investigation of sensory neuronal function and nociception. In vitro imaging of acutely dissociated sensory neurons using membrane-permeant fluorescent Ca²⁺ indicators remains the most common approach to study Ca²⁺ signalling in sensory neurons. Fluo4 is a popular choice of single-wavelength indicator due to its brightness, high affinity for Ca²⁺ and ease of use. However, unlike ratiometric indicators, the emission intensity from single-wavelength indicators can be affected by indicator concentration, optical path length, excitation intensity and detector efficiency. As such, without careful calibration, it can be difficult to draw inferences from differences in the magnitude of Ca²⁺ transients recorded using Fluo4. Here, we show that a method scarcely used in sensory neurophysiology - first proposed by Maravall and colleagues (2000) - can provide reliable estimates of absolute cytosolic Ca²⁺ concentration ([Ca²⁺]_cyt) in acutely dissociated sensory neurons using Fluo4. This method is straightforward to implement; is applicable to any high-affinity single-wavelength Ca²⁺ indicator with a large dynamic range; and provides estimates of [Ca²⁺]_cyt in line with other methods, including ratiometric imaging. Use of this method will improve the granularity of sensory neuron Ca²⁺ imaging data obtained with Fluo4.</p>","PeriodicalId":19010,"journal":{"name":"Molecular Pain","volume":"20 ","pages":"17448069241230420"},"PeriodicalIF":3.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10880540/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139913102","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to \"Oxytocin inhibits hindpaw hyperalgesia induced by orofacial inflammation combined with stress\".","authors":"","doi":"10.1177/17448069241281005","DOIUrl":"10.1177/17448069241281005","url":null,"abstract":"","PeriodicalId":19010,"journal":{"name":"Molecular Pain","volume":"20 ","pages":"17448069241281005"},"PeriodicalIF":2.8,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11457178/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142350550","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reduced capsaicin-induced mechanical allodynia and neuronal responses in the dorsal root ganglion in the presence of protein tyrosine phosphatase non-receptor type 6 overexpression.","authors":"Robin Vroman, Shingo Ishihara, Spencer Fullam, Matthew J Wood, Natalie S Adamczyk, Nolan Lomeli, Fransiska Malfait, Anne-Marie Malfait, Rachel E Miller, Adrienn Markovics","doi":"10.1177/17448069241258106","DOIUrl":"10.1177/17448069241258106","url":null,"abstract":"<p><p>Transient Receptor Potential Vanilloid 1 (TRPV1) is a nonselective cation channel expressed by pain-sensing neurons and has been an attractive target for the development of drugs to treat pain. Recently, Src homology region two domain-containing phosphatase-1 (SHP-1, encoded by <i>Ptpn6</i>) was shown to dephosphorylate TRPV1 in dorsal root ganglia (DRG) neurons, which was linked with alleviating different pain phenotypes. These previous studies were performed in male rodents only and did not directly investigate the role of SHP-1 in TRPV-1 mediated sensitization. Therefore, our goal was to determine the impact of <i>Ptpn6</i> overexpression on TRPV1-mediated neuronal responses and capsaicin-induced pain behavior in mice of both sexes. Twelve-week-old male and female mice overexpressing <i>Ptpn6</i> (Shp1-Tg) and their wild type (WT) littermates were used. <i>Ptpn6</i> overexpression was confirmed in the DRG of Shp1-Tg mice by RNA in situ hybridization and RT-qPCR. <i>Trpv1</i> and <i>Ptpn6</i> were found to be co-expressed in DRG sensory neurons in both genotypes. Functionally, this overexpression resulted in lower magnitude intracellular calcium responses to 200 nM capsaicin stimulation in DRG cultures from Shp1-Tg mice compared to WTs. <i>In</i> <i>vivo</i>, we tested the effects of <i>Ptpn6</i> overexpression on capsaicin-induced pain through a model of capsaicin footpad injection. While capsaicin injection evoked nocifensive behavior (paw licking) and paw swelling in both genotypes and sexes, only WT mice developed mechanical allodynia after capsaicin injection. We observed similar level of TRPV1 protein expression in the DRG of both genotypes, however, a higher amount of tyrosine phosphorylated TRPV1 was detected in WT DRG. These experiments suggest that, while SHP-1 does not mediate the acute swelling and nocifensive behavior induced by capsaicin, it does mediate a protective effect against capsaicin-induced mechanical allodynia in both sexes. The protective effect of SHP-1 might be mediated by TRPV1 dephosphorylation in capsaicin-sensitive sensory neurons of the DRG.</p>","PeriodicalId":19010,"journal":{"name":"Molecular Pain","volume":" ","pages":"17448069241258106"},"PeriodicalIF":2.8,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11273697/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140945634","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A microfluidic model of the first sensory synapse for analgesic target discovery.","authors":"Georgios Kimourtzis, Ramin Raouf","doi":"10.1177/17448069241293286","DOIUrl":"10.1177/17448069241293286","url":null,"abstract":"<p><p>The synaptic connections between dorsal root ganglia (DRG) and dorsal horn (DH) neurons are a crucial relay point for the transmission of painful stimuli. To delineate how synaptic plasticity may modulate the excitability of DH neurons, we have devised a microfluidic co-culture model that recapitulates the first sensory synapse using postnatal mouse sensory neurons. We show that DRG-DH co-cultures characterize salient features of the in vivo physiology of sensory neurons. Immunocytcochemical experiments of the cultured DH neurons show a co-localization of Map2 with VGlut2 and of Map2 with Synapsin 1, corroborating the glutamatergic identity of the DH neurons and further suggesting the potential formation of active synapses in this neuronal set. Fluorometric imaging experiments demonstrate the elicitation of calcium responses in DH neurons following the stimulation of DRG cell bodies or axons. Selective NMDA and AMPA receptor blockade appreciably silences DH neuron responses, suggesting that glutamatergic signaling is maintained in vitro. Last, a surrogate model of peripheral nerve injury is introduced in the form of an axotomy, which results in elevated and prolonged calcium responses of DH neurons. Overall, the microfluidic mouse co-cultures provide a method advancement in the study of periphery-to-center pain signaling, where the potential of utilizing the platform for drug target identification is underscored.</p>","PeriodicalId":19010,"journal":{"name":"Molecular Pain","volume":" ","pages":"17448069241293286"},"PeriodicalIF":4.6,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11565614/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470490","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}