Research

18 pages, 5371 KiB

Open AccessArticle

Catecholaminergic and Cholinergic Systems Mediate Beneficial Effect of Vortioxetine on Diabetes-Induced Neuropathic Pain

by Nazlı Turan Yücel, Ümmühan Kandemir, Umut İrfan Üçel, Ümide Demir Özkay and Özgür Devrim Can

Biomedicines 2023, 11(4), 1137; https://doi.org/10.3390/biomedicines11041137 - 10 Apr 2023

Viewed by 1683

Abstract

The therapeutic potential of vortioxetine on mechanical hyperalgesia/allodynia was investigated in rats with streptozotocin-induced diabetes, and its possible mechanism of action was elucidated in this study. The obtained findings demonstrated that subacute vortioxetine treatment (5 and 10 mg/kg for 2 weeks) increased the [...] Read more.

The therapeutic potential of vortioxetine on mechanical hyperalgesia/allodynia was investigated in rats with streptozotocin-induced diabetes, and its possible mechanism of action was elucidated in this study. The obtained findings demonstrated that subacute vortioxetine treatment (5 and 10 mg/kg for 2 weeks) increased the reduced paw-withdrawal thresholds of diabetic rats both in the Randall–Selitto and Dynamic plantar tests. Moreover, the falling latencies of animals did not change in the Rota-rod assessments. These results suggest that vortioxetine administration significantly improved diabetes-induced hyperalgesia and allodynia responses in the rats without affecting their motor coordination. The vortioxetine (5 mg/kg)-induced antihyperalgesic and antiallodynic effects were reversed by AMPT, yohimbine, ICI 118,551, sulpiride and atropine pre-treatments, suggesting the involvement of the catecholaminergic system, α₂- and β₂-adrenoceptors, D_2/3 dopaminergic receptors and cholinergic muscarinic receptors in the exhibited pharmacological activity, respectively. Moreover, the data from the immunohistochemical studies indicated that the inhibition of c-Fos overexpression in dorsal horn neurons also mediates the beneficial effect of this drug. Vortioxetine induced no difference in plasma glucose levels in diabetic rats. If clinical studies confirm these findings, the concomitant beneficial effect of vortioxetine on mood disorders and its neutral activity profile on glycemic control may make it an alternative drug for the treatment of neuropathic pain. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Chronic Pain and New Therapeutic Strategies)

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11 pages, 2688 KiB

Open AccessArticle

Effectiveness and Safety of Belimumab in Chinese Lupus Patients: A Multicenter, Real-World Observational Study

by Fangfang Sun, Huaxiang Wu, Zitao Wang, Tong Wu, Xue Wu, Jie Chen, Danting Zhang, Chunde Bao, Nan Shen, Lijun Wu, Jing Zhu and Shuang Ye

Biomedicines 2023, 11(3), 962; https://doi.org/10.3390/biomedicines11030962 - 21 Mar 2023

Cited by 2 | Viewed by 2572

Abstract

Objective: The effectiveness and safety of belimumab in Chinese lupus patients with different disease activities were investigated in a real-world setting. Method: Patients who received 10 mg/kg belimumab intravenously on weeks 0, 2, and 4, and then every 4 weeks on [...] Read more.

Objective: The effectiveness and safety of belimumab in Chinese lupus patients with different disease activities were investigated in a real-world setting. Method: Patients who received 10 mg/kg belimumab intravenously on weeks 0, 2, and 4, and then every 4 weeks on a background of standard-of-care (SoC) therapy and had a follow-up of more than 6 months were enrolled from four centers in China. They were stratified according to the Safety of Estrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index (SELENA-SLEDAI) score at baseline as the moderate/severe (SELENA-SLEDAI > 6) or mild subgroups (SELENA-SLEDAI ≤ 6). Attainment of the Lupus Low Disease Activity State (LLDAS) or remission on treatment was analyzed in all patients. The SLE Responder Index 4 (SRI-4) and SELENA-SLEDAI Flare Index (SFI) were evaluated for patients with moderate/severe disease and mild disease, respectively. Patients in the control arm with SoC alone from previous metformin lupus trials were selected by propensity score matching (PSM) as the reference group. Results: 224 SLE patients with a mean follow-up of 11.7 months receiving belimumab were enrolled in this observational study, of which 126 and 98 were in the moderate/severe and mild subgroup, respectively. At 12 months, 54.76% of the patients attained LLDAS and 28.57% attained remission. Lower daily prednisone at baseline were independently associated with 12-month LLDAS. Further, 87% of the subgroup with moderate/severe disease achieved SRI-4 at 12 months and a high SLEDAI at baseline was its predictive factor. For the mild subgroup, a reduced flare rate was observed compared with PSM reference (17.5%, vs. 38.6%, p = 0.021). Infection events, particularly viral infections and pneumonia were recorded in 7 and 6 patients, respectively. Conclusion: Our real-world data supported the effectiveness and safety of belimumab in Chinese lupus patients. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Chronic Pain and New Therapeutic Strategies)

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21 pages, 5310 KiB

Open AccessArticle

Sex Differences in the Expression of Neuroimmune Molecules in the Spinal Cord of a Mouse Model of Antiretroviral-Induced Neuropathic Pain

by Maryam W. Al-HadlaQ and Willias Masocha

Biomedicines 2023, 11(3), 875; https://doi.org/10.3390/biomedicines11030875 - 13 Mar 2023

Cited by 2 | Viewed by 1587

Abstract

Nucleoside reverse transcriptase inhibitors (NRTIs), drugs used to treat HIV infection, can cause neuropathic pain (NP) and neuroinflammation. An NRTI, 2′-3′-dideoxycytidine (ddC), was reported to induce mechanical allodynia and increase proinflammatory cytokines in the brains of female mice. In some models of NP, [...] Read more.

Nucleoside reverse transcriptase inhibitors (NRTIs), drugs used to treat HIV infection, can cause neuropathic pain (NP) and neuroinflammation. An NRTI, 2′-3′-dideoxycytidine (ddC), was reported to induce mechanical allodynia and increase proinflammatory cytokines in the brains of female mice. In some models of NP, microglia activation is important for NP pathophysiology in male mice, while T cells are important in female mice. Age-matched female and male mice (BALB/c strain) treated intraperitoneally once daily with ddC for 5 days developed mechanical allodynia. Treatment with ddC increased Cd11b, H2-Aa, Cd3e, Mapk1, Il1b, Tnf, and Il10 mRNA levels in the spinal cords of female, but not male, mice, whereas there was no alteration found in Gfap and Mapk14 transcripts in both sexes on day 7 after ddC administration. The protein expression of CD11b and phospho-p38 MAPK was significantly increased in the spinal cords of ddC-treated female, but not male, mice, whereas Iba1 protein was elevated in ddC-treated male mice. There was no change in GFAP, CD3e, and phospho-p44/42 MAPK protein levels in both sexes. Thus, changes in neuroimmune cells and molecules in the spinal cords during ddC-induced neuroinflammation were sex-dependent, with female mice being more prone to neuroimmune changes than male mice. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Chronic Pain and New Therapeutic Strategies)

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20 pages, 5690 KiB

Open AccessArticle

Inflammatory Blood Signature Related to Common Psychological Comorbidity in Chronic Pain

by Bianka Karshikoff, Karin Wåhlén, Jenny Åström, Mats Lekander, Linda Holmström and Rikard K. Wicksell

Biomedicines 2023, 11(3), 713; https://doi.org/10.3390/biomedicines11030713 - 27 Feb 2023

Cited by 3 | Viewed by 1962

Abstract

Chronic pain is characterized by high psychological comorbidity, and diagnoses are symptom-based due to a lack of clear pathophysiological factors and valid biomarkers. We investigate if inflammatory blood biomarker signatures are associated with pain intensity and psychological comorbidity in a mixed chronic pain [...] Read more.

Chronic pain is characterized by high psychological comorbidity, and diagnoses are symptom-based due to a lack of clear pathophysiological factors and valid biomarkers. We investigate if inflammatory blood biomarker signatures are associated with pain intensity and psychological comorbidity in a mixed chronic pain population. Eighty-one patients (72% women) with chronic pain (>6 months) were included. Patient reported outcomes were collected, and blood was analyzed with the Proseek Multiplex Olink Inflammation Panel (Bioscience Uppsala, Uppsala, Sweden), resulting in 77 inflammatory markers included for multivariate data analysis. Three subgroups of chronic pain patients were identified using an unsupervised principal component analysis. No difference between the subgroups was seen in pain intensity, but differences were seen in mental health and inflammatory profiles. Ten inflammatory proteins were significantly associated with anxiety and depression (using the Generalized Anxiety Disorder 7-item scale (GAD-7) and the Patient Health Questionnaire (PHQ-9): STAMBP, SIRT2, AXIN1, CASP-8, ADA, IL-7, CD40, CXCL1, CXCL5, and CD244. No markers were related to pain intensity. Fifteen proteins could differentiate between patients with moderate/high (GAD-7/PHQ-9 > 10) or mild/no (GAD-7/PHQ-9 < 10) psychological comorbidity. This study further contributes to the increasing knowledge of the importance of inflammation in chronic pain conditions and indicates that specific inflammatory proteins may be related to psychological comorbidity. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Chronic Pain and New Therapeutic Strategies)

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24 pages, 3079 KiB

Open AccessArticle

Effects of NADPH Oxidase Isoform-2 (NOX2) Inhibition on Behavioral Responses and Neuroinflammation in a Mouse Model of Neuropathic Pain

by Luísa Teixeira-Santos, Eduardo Veríssimo, Sandra Martins, Teresa Sousa, António Albino-Teixeira and Dora Pinho

Biomedicines 2023, 11(2), 416; https://doi.org/10.3390/biomedicines11020416 - 31 Jan 2023

Cited by 2 | Viewed by 1651

Abstract

NADPH oxidase isoform-2 (NOX2) has been implicated in the pathophysiology of neuropathic pain (NP), mostly through the modulation of neuroinflammation. Since it is also accepted that some neuroimmune mechanisms underlying NP are sex-dependent, we aimed to evaluate the effects of early systemic treatment [...] Read more.

NADPH oxidase isoform-2 (NOX2) has been implicated in the pathophysiology of neuropathic pain (NP), mostly through the modulation of neuroinflammation. Since it is also accepted that some neuroimmune mechanisms underlying NP are sex-dependent, we aimed to evaluate the effects of early systemic treatment with the NOX2-selective inhibitor (NOX2i) GSK2795039 on behavioral responses and spinal neuroinflammation in spared nerve injury (SNI)-induced NP in male and female mice. Mechanical sensitivity was evaluated with the von Frey test, while general well-being and anxiety-like behavior were assessed with burrowing and light/dark box tests. Spinal microglial activation and cytokines IL-1β, IL-6, and IL-10, as well as macrophage colony-stimulating factor (M-CSF) were evaluated by immunofluorescence and multiplex immunoassay, respectively. NOX2i treatment reduced SNI-induced mechanical hypersensitivity and early SNI-induced microglial activation in both sexes. SNI-females, but not males, showed a transient reduction in burrowing activity. NOX2i treatment did not improve their burrowing activity, but tendentially reduced their anxiety-like behavior. NOX2i marginally decreased IL-6 in females, and increased M-CSF in males. Our findings suggest that NOX2-selective inhibition may be a potential therapeutic strategy for NP in both male and female individuals, with particular interest in females due to its apparent favorable impact in anxiety-like behavior. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Chronic Pain and New Therapeutic Strategies)

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Review

Jump to: Research, Other

15 pages, 332 KiB

Open AccessReview

The Association between Dysbiosis and Neurological Conditions Often Manifesting with Chronic Pain

by Mary Garvey

Biomedicines 2023, 11(3), 748; https://doi.org/10.3390/biomedicines11030748 - 01 Mar 2023

Cited by 6 | Viewed by 1910

Abstract

The prevalence of neurological conditions which manifest with chronic pain is increasing globally, where the World Health Organisation has now classified chronic pain as a risk factor for death by suicide. While many chronic pain conditions have a definitive underlying aetiology, non-somatic conditions [...] Read more.

The prevalence of neurological conditions which manifest with chronic pain is increasing globally, where the World Health Organisation has now classified chronic pain as a risk factor for death by suicide. While many chronic pain conditions have a definitive underlying aetiology, non-somatic conditions represent difficult-to-diagnose and difficult-to-treat public health issues. The interaction of the immune system and nervous system has become an important area in understanding the occurrence of neuroinflammation, nociception, peripheral and central sensitisation seen in chronic pain. More recently, however, the role of the resident microbial species in the human gastrointestinal tract has become evident. Dysbiosis, an alteration in the microbial species present in favour of non-beneficial and pathogenic species has emerged as important in many chronic pain conditions, including functional somatic syndromes, autoimmune disease and neurological diseases. In particular, a decreased abundance of small chain fatty acid, e.g., butyrate-producing bacteria, including Faecalibacterium, Firmicutes and some Bacteroides spp., is frequently evident in morbidities associated with long-term pain. Microbes involved in the production of neurotransmitters serotonin, GABA, glutamate and dopamine, which mediate the gut-brain, axis are also important. This review outlines the dysbiosis present in many disease states manifesting with chronic pain, where an overlap in morbidities is also frequently present in patients. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Chronic Pain and New Therapeutic Strategies)

19 pages, 1967 KiB

Open AccessReview

Synaptic Plasticity in the Pain-Related Cingulate and Insular Cortex

by Jung-Hyun Alex Lee, Qiyu Chen and Min Zhuo

Biomedicines 2022, 10(11), 2745; https://doi.org/10.3390/biomedicines10112745 - 28 Oct 2022

Cited by 16 | Viewed by 2213

Abstract

Cumulative animal and human studies have consistently demonstrated that two major cortical regions in the brain, namely the anterior cingulate cortex (ACC) and insular cortex (IC), play critical roles in pain perception and chronic pain. Neuronal synapses in these cortical regions of adult [...] Read more.

Cumulative animal and human studies have consistently demonstrated that two major cortical regions in the brain, namely the anterior cingulate cortex (ACC) and insular cortex (IC), play critical roles in pain perception and chronic pain. Neuronal synapses in these cortical regions of adult animals are highly plastic and can undergo long-term potentiation (LTP), a phenomenon that is also reported in brain areas for learning and memory (such as the hippocampus). Genetic and pharmacological studies show that inhibiting such cortical LTP can help to reduce behavioral sensitization caused by injury as well as injury-induced emotional changes. In this review, we will summarize recent progress related to synaptic mechanisms for different forms of cortical LTP and their possible contribution to behavioral pain and emotional changes. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Chronic Pain and New Therapeutic Strategies)

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Other

Jump to: Research, Review

23 pages, 1129 KiB

Open AccessSystematic Review

Tendinopathies and Pain Sensitisation: A Meta-Analysis with Meta-Regression

by Davide Previtali, Alberto Mameli, Stefano Zaffagnini, Paolo Marchettini, Christian Candrian and Giuseppe Filardo

Biomedicines 2022, 10(7), 1749; https://doi.org/10.3390/biomedicines10071749 - 20 Jul 2022

Cited by 4 | Viewed by 1956

Abstract

The presence of pain sensitisation has been documented and reported as being a possible cause of treatment failure and pain chronicity in several musculoskeletal conditions, such as tendinopathies. The aim of the present study is to analyse existing evidence on pain sensitisation in [...] Read more.

The presence of pain sensitisation has been documented and reported as being a possible cause of treatment failure and pain chronicity in several musculoskeletal conditions, such as tendinopathies. The aim of the present study is to analyse existing evidence on pain sensitisation in tendinopathies comparing the local and distant pain thresholds of healthy and affected subjects with distinct analysis for different tendinopathies. PubMed, Cochrane Central Register, Scopus, and Web Of Science were systematically searched after registration on PROSPERO (CRD42020164124). Level I to level IV studies evaluating the presence of pain sensitisation in patients with symptomatic tendinopathies, documented through a validated method, were included. A meta-analysis was performed to compare local, contralateral, and distant pain thresholds between patients and healthy controls with sub-analyses for different tendinopathies. Meta-regressions were conducted to evaluate the influence of age, activity level, and duration of symptoms on results. Thirty-four studies out of 2868 were included. The overall meta-analysis of local pressure pain thresholds (PPT) documented an increased sensitivity in affected subjects (p < 0.001). The analyses on contralateral PPTs (p < 0.001) and distant PPTs (p = 0.009) documented increased sensitivity in the affected group. The results of the sub-analyses on different tendinopathies were conflicting, except for those on lateral epicondylalgia. Patients’ activity level (p = 0.02) and age (p = 0.05) significantly influenced local PPT results. Tendinopathies are characterized by pain sensitisation, but, while features of both central and peripheral sensitisation can be constantly detected in lateral epicondylalgia, results on other tendinopathies were more conflicting. Patients’ characteristics are possible confounders that should be taken into account when addressing pain sensitisation. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Chronic Pain and New Therapeutic Strategies)

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