Submit to IJMS Review for IJMS Propose a Special Issue

Journal Menu

Journal Browser

The Multiple Mechanisms Underlying Neuropathic Pain (III)

Special Issue Editors
Special Issue Information
Keywords
Benefits of Publishing in a Special Issue
Published Papers

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (20 August 2024) | Viewed by 12162

Share This Special Issue

Special Issue Editors

Dr. Roberto Coccurello

E-Mail Website
Guest Editor

European Centre for Brain Research, IRCCS - Santa Lucia Foundation (FSL), National Research Council (C.N.R.) Institute for Complex System (ISC), Via del Fosso di Fiorano 64, 00143 Roma, Italy
Interests: nutrition; obesity; energy metabolism; brain reward processing; gut-brain axis; neuropathic pain; neurodegenerative diseases; neuroinflammation
Special Issues, Collections and Topics in MDPI journals

Dr. Sara Marinelli

E-Mail Website
Guest Editor

National Research Council (C.N.R.) Institute of Biochemistry and Cell Biology (IBBC), Campus Internazionale "Adriano Buzzati-Traverso", Via E. Ramarini, 32, 00015 Monterotondo Scalo, Roma, Italy
Interests: neuropathy; pain; autophagy; myelin; glia; disease-related biomarkers; immune cells; inflammation
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Pain is a highly subjective, barely communicable, conscious experience—a form of private knowledge including sensorial, cognitive, and affective evaluation and processing. The switch from acute to chronic pain is characterized by the passage between noxious stimuli and pain as a defense of the body’s integrity and persistent pain as a clinical syndrome. Indeed, neuropathic pain (NeP) comprises different clinical signs and symptoms and many sites (e.g., from peripheral sensory fibers to cortical brain areas) of possible injuries. Multiple causes, such as polyneuropathy and small-fiber neuropathy of different origin, and multiple mechanisms are established features in NeP.

There is increasing awareness that the dysregulation of multiple molecular, metabolic, and biochemical pathways can significantly contribute to chronic neuroinflammation and to the development of NeP. In parallel, there is also growing attention toward the different clinical impact produced by neuropathies on male and female subjects in both medical settings and in rodent models. As a matter of fact, pain does not affect male and female individuals in the same manner, and sex differences in pain responses are well-recognized clinical facts. Although several factors (e.g., genetic, hormonal, physiological, and neuronal) and signaling pathways (e.g., Toll-like receptors, immune cells) have been identified to be involved in pain processing in a sex-dependent fashion, our view is still limited and not adequately advanced to develop effective sex-specific antinociceptive treatments. Gender differences in pain perception and relief dramatically modify analgesic response, drug efficacy, and the management of chronic pain.

Based on these grounds, in the present Special Issue, we invite original research and reviews in the field of mechanisms underlying NeP, including neuroinflammatory aspects and sexual dimorphism in response to painkillers. The SI will particularly address molecular, biochemical, and metabolic mechanisms and the evidence of pain behaviors that may help to increase our knowledge of NeP pathophysiology and contribute to account for sex-dependent differences in pain experience.

Dr. Roberto Coccurello
Dr. Sara Marinelli
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

neuropathic pain
nociception
neuroinflammation
sex differences
sex hormones
analgesic response

Benefits of Publishing in a Special Issue

Ease of navigation: Grouping papers by topic helps scholars navigate broad scope journals more efficiently.
Greater discoverability: Special Issues support the reach and impact of scientific research. Articles in Special Issues are more discoverable and cited more frequently.
Expansion of research network: Special Issues facilitate connections among authors, fostering scientific collaborations.
External promotion: Articles in Special Issues are often promoted through the journal's social media, increasing their visibility.
e-Book format: Special Issues with more than 10 articles can be published as dedicated e-books, ensuring wide and rapid dissemination.

Further information on MDPI's Special Issue polices can be found here.

Published Papers (7 papers)

Download All Papers

Order results

Result details

Show export options Show export options

Select all

Export citation of selected articles as:

Research

Jump to: Review

17 pages, 7786 KiB

Open AccessArticle

Electroacupuncture Relieves Neuropathic Pain via Adenosine 3 Receptor Activation in the Spinal Cord Dorsal Horn of Mice

by Faisal Ayub Kiani, Hao Li, Sha Nan, Qiuhua Li, Qianghui Lei, Ruiling Yin, Shiya Cao, Mingxing Ding and Yi Ding

Int. J. Mol. Sci. 2024, 25(19), 10242; https://doi.org/10.3390/ijms251910242 - 24 Sep 2024

Viewed by 1021

Abstract

Neuropathic pain (NPP) is a devastating and unbearable painful condition. As prevailing treatment strategies have failed to mitigate its complications, there remains a demand for effective therapies. Electroacupuncture (EA) has proved a potent remedial strategy in NPP management in humans and mammals. However, past studies have investigated the underlying mechanism of the analgesic effects of EA on NPP, focusing primarily on adenosine receptors in peripheral tissues. Herein, we elucidate the role of the adenosine (Adora-3) signaling pathway in mediating pain relief through EA in the central nervous system, which is obscure in the literature and needs exploration. Specific pathogen-free (SPF) male adult mice (C57BL/6 J) were utilized to investigate the effect of EA on adenosine metabolism (CD73, ADA) and its receptor activation (Adora-3), as potential mechanisms to mitigate NPP in the central nervous system. NPP was induced via spared nerve injury (SNI). EA treatment was administered seven times post-SNI surgery, and lumber (L4–L6) spinal cord was collected to determine the molecular expression of mRNA and protein levels. In the spinal cord of mice, following EA application, the expression results revealed that EA upregulated (p < 0.05) Adora-3 and CD73 by inhibiting ADA expression. In addition, EA triggered the release of adenosine (ADO), which modulated the nociceptive responses and enhanced neuronal activation. Meanwhile, the interplay between ADO levels and EA-induced antinociception, using an Adora-3 agonist and antagonist, showed that the Adora-3 agonist IB-MECA significantly increased (p < 0.05) nociceptive thresholds and expression levels. In contrast, the antagonist MRS1523 exacerbated neuropathic pain. Furthermore, an upregulated effect of EA on Adora-3 expression was inferred when the Adora-3 antagonist was administered, and the EA treatment increased the fluorescent intensity of Adora-3 in the spinal cord. Taken together, EA effectively modulates NPP by regulating the Adora-3 signaling pathway under induced pain conditions. These findings enhance our understanding of NPP management and offer potential avenues for innovative therapeutic interventions. Full article

(This article belongs to the Special Issue The Multiple Mechanisms Underlying Neuropathic Pain (III))

► Show Figures

Graphical abstract

16 pages, 5022 KiB

Open AccessArticle

The Role of the Mu Opioid Receptors of the Medial Prefrontal Cortex in the Modulation of Analgesia Induced by Acute Restraint Stress in Male Mice

by Yinan Du, Yukui Zhao, Aozhuo Zhang, Zhiwei Li, Chunling Wei, Qiaohua Zheng, Yanning Qiao, Yihui Liu, Wei Ren, Jing Han, Zongpeng Sun, Weiping Hu and Zhiqiang Liu

Int. J. Mol. Sci. 2024, 25(18), 9774; https://doi.org/10.3390/ijms25189774 - 10 Sep 2024

Viewed by 1020

Abstract

Mu opioid receptors (MORs) represent a vital mechanism related to the modulation of stress-induced analgesia (SIA). Previous studies have reported on the gamma-aminobutyric acid (GABA)ergic “disinhibition” mechanisms of MORs on the descending pain modulatory pathway of SIA induced in the midbrain. However, the role of the MORs expressed in the medial prefrontal cortex (mPFC), one of the main cortical areas participating in pain modulation, in SIA remains completely unknown. In this study, we investigated the contributions of MORs expressed on glutamatergic (MORGlut) and GABAergic (MORGABA) neurons of the medial prefrontal cortex (mPFC), as well as the functional role and activity of neurons projecting from the mPFC to the periaqueductal gray (PAG) region, in male mice. We achieved this through a combination of hot-plate tests, c-fos staining, and 1 h acute restraint stress exposure tests. The results showed that our acute restraint stress protocol produced mPFC MOR-dependent SIA effects. In particular, MORGABA was found to play a major role in modulating the effects of SIA, whereas MORGlut seemed to be unconnected to the process. We also found that mPFC–PAG projections were efficiently activated and played key roles in the effects of SIA, and their activation was mediated by MORGABA to a large extent. These results indicated that the activation of mPFC MORGABA due to restraint stress was able to activate mPFC–PAG projections in a potential “disinhibition” pathway that produced analgesic effects. These findings provide a potential theoretical basis for pain treatment or drug screening targeting the mPFC. Full article

(This article belongs to the Special Issue The Multiple Mechanisms Underlying Neuropathic Pain (III))

► Show Figures

Figure 1

18 pages, 12857 KiB

Open AccessArticle

Dynamics of Cellular Regulation of Fractalkine/CX3CL1 and Its Receptor CX3CR1 in the Rat Trigeminal Subnucleus Caudalis after Unilateral Infraorbital Nerve Lesion—Extended Cellular Signaling of the CX3CL1/CX3CR1 Axis in the Development of Trigeminal Neuropathic Pain

by Lucie Kubíčková and Petr Dubový

Int. J. Mol. Sci. 2024, 25(11), 6069; https://doi.org/10.3390/ijms25116069 - 31 May 2024

Cited by 2 | Viewed by 892

Abstract

The cellular distribution and changes in CX3CL1/fractalkine and its receptor CX3CR1 protein levels in the trigeminal subnucleus caudalis (TSC) of rats with unilateral infraorbital nerve ligation (IONL) were investigated on postoperation days 1, 3, 7, and 14 (POD1, POD3, POD7, and POD14, respectively) and compared with those of sham-operated and naïve controls. Behavioral tests revealed a significant increase in tactile hypersensitivity bilaterally in the vibrissal pads of both sham- and IONL-operated animals from POD1 to POD7, with a trend towards normalization in sham controls at POD14. Image analysis revealed increased CX3CL1 immunofluorescence (IF) intensities bilaterally in the TSC neurons of both sham- and IONL-operated rats at all survival periods. Reactive astrocytes in the ipsilateral TSC also displayed CX3CL1-IF from POD3 to POD14. At POD1 and POD3, microglial cells showed high levels of CX3CR1-IF, which decreased by POD7 and POD14. Conversely, CX3CR1 was increased in TSC neurons and reactive astrocytes at POD7 and POD14, which coincided with high levels of CX3CL1-IF and ADAM17-IF. This indicates that CX3CL1/CX3CR1 may be involved in reciprocal signaling between TSC neurons and reactive astrocytes. The level of CatS-IF in microglial cells suggests that soluble CX3CL1 may be involved in neuron–microglial cell signaling at POD3 and POD7, while ADAM17 allows this release at all studied time points. These results indicate an extended CX3CL1/CX3CR1 signaling axis and its role in the crosstalk between TSC neurons and glial cells during the development of trigeminal neuropathic pain. Full article

(This article belongs to the Special Issue The Multiple Mechanisms Underlying Neuropathic Pain (III))

► Show Figures

Figure 1

20 pages, 1886 KiB

Open AccessArticle

Analgesic Effects of Fisetin, Peimine, Astaxanthin, Artemisinin, Bardoxolone Methyl and 740 Y-P and Their Influence on Opioid Analgesia in a Mouse Model of Neuropathic Pain

by Katarzyna Ciapała, Ewelina Rojewska, Katarzyna Pawlik, Agata Ciechanowska and Joanna Mika

Int. J. Mol. Sci. 2023, 24(10), 9000; https://doi.org/10.3390/ijms24109000 - 19 May 2023

Cited by 10 | Viewed by 2849

Abstract

Treatment of neuropathic pain remains a challenge for modern medicine due to the insufficiently understood molecular mechanisms of its development and maintenance. One of the most important cascades that modulate the nociceptive response is the family of mitogen-activated protein (MAP) kinases and phosphatidylinositol-3-kinase (PI3K), as well as nuclear factor erythroid 2-related factor 2 (Nrf2). The aim of this study was to determine the effect of nonselective modulators of MAP kinases—fisetin (ERK1/2 and NFκB inhibitor, PI3K activator), peimine (MAPK inhibitor), astaxanthin (MAPK inhibitor, Nrf2 activator) and artemisinin (MAPK inhibitor, NFκB activator), as well as bardoxolone methyl (selective activator of Nrf2) and 740 Y-P (selective activator of PI3K)—in mice with peripheral neuropathy and to compare their antinociceptive potency and examine their effect on analgesia induced by opioids. The study was performed using albino Swiss male mice that were exposed to chronic constriction injury of the sciatic nerve (CCI model). Tactile and thermal hypersensitivity was measured using von Frey and cold plate tests, respectively. Single doses of substances were administered intrathecally on day 7 after CCI. Among the tested substances, fisetin, peimine, and astaxanthin effectively diminished tactile and thermal hypersensitivity in mice after CCI, while artemisinin did not exhibit analgesic potency in this model of neuropathic pain. Additionally, both of the activators tested, bardoxolone methyl and 740 Y-P, also showed analgesic effects after intrathecal administration in mice exposed to CCI. In the case of astaxanthin and bardoxolone methyl, an increase in analgesia after combined administration with morphine, buprenorphine, and/or oxycodone was observed. Fisetin and peimine induced a similar effect on tactile hypersensitivity, where analgesia was enhanced after administration of morphine or oxycodone. In the case of 740 Y-P, the effects of combined administration with each opioid were observed only in the case of thermal hypersensitivity. The results of our research clearly indicate that substances that inhibit all three MAPKs provide pain relief and improve opioid effectiveness, especially if they additionally block NF-κB, such as peimine, inhibit NF-κB and activate PI3K, such as fisetin, or activate Nrf2, such as astaxanthin. In light of our research, Nrf2 activation appears to be particularly beneficial. The abovementioned substances bring promising results, and further research on them will broaden our knowledge regarding the mechanisms of neuropathy and perhaps contribute to the development of more effective therapy in the future. Full article

(This article belongs to the Special Issue The Multiple Mechanisms Underlying Neuropathic Pain (III))

► Show Figures

Graphical abstract

Review

Jump to: Research

18 pages, 1318 KiB

Open AccessReview

Navigating the Controversies: Role of TRPM Channels in Pain States

by Maria A. Gandini and Gerald W. Zamponi

Int. J. Mol. Sci. 2024, 25(19), 10284; https://doi.org/10.3390/ijms251910284 - 24 Sep 2024

Viewed by 1211

Abstract

Chronic pain is a debilitating condition that affects up to 1.5 billion people worldwide and bears a tremendous socioeconomic burden. The success of pain medicine relies on our understanding of the type of pain experienced by patients and the mechanisms that give rise to it. Ion channels are among the key targets for pharmacological intervention in chronic pain conditions. Therefore, it is important to understand how changes in channel properties, trafficking, and molecular interactions contribute to pain sensation. In this review, we discuss studies that have demonstrated the involvement of transient receptor potential M2, M3, and M8 channels in pain generation and transduction, as well as the controversies surrounding these findings. Full article

(This article belongs to the Special Issue The Multiple Mechanisms Underlying Neuropathic Pain (III))

► Show Figures

Graphical abstract

17 pages, 1738 KiB

Open AccessReview

The Locus Coeruleus in Chronic Pain

by Jorge Castejón España, Anusha Yasoda-Mohan and Sven Vanneste

Int. J. Mol. Sci. 2024, 25(16), 8636; https://doi.org/10.3390/ijms25168636 - 8 Aug 2024

Viewed by 1931

Abstract

Pain perception is the consequence of a complex interplay between activation and inhibition. Noradrenergic pain modulation inhibits nociceptive transmission and pain perception. The main source of norepinephrine (NE) in the central nervous system is the Locus Coeruleus (LC), a small but complex cluster of cells in the pons. The aim of this study is to review the literature on the LC-NE inhibitory system, its influence on chronic pain pathways and its frequent comorbidities. The literature research showed that pain perception is the consequence of nociceptive and environmental processing and is modulated by the LC-NE system. If perpetuated in time, nociceptive inputs can generate neuroplastic changes in the central nervous system that reduce the inhibitory effects of the LC-NE complex and facilitate the development of chronic pain and frequent comorbidities, such as anxiety, depression or sleeping disturbances. The exact mechanisms involved in the LC functional shift remain unknown, but there is some evidence that they occur through plastic changes in the medial and lateral pathways and their brain projections. Additionally, there are other influencing factors, like developmental issues, neuroinflammatory glial changes, NE receptor affinity and changes in LC neuronal firing rates. Full article

(This article belongs to the Special Issue The Multiple Mechanisms Underlying Neuropathic Pain (III))

► Show Figures

Figure 1

45 pages, 1885 KiB

Open AccessReview

CC Chemokine Family Members’ Modulation as a Novel Approach for Treating Central Nervous System and Peripheral Nervous System Injury—A Review of Clinical and Experimental Findings

by Agata Ciechanowska and Joanna Mika

Int. J. Mol. Sci. 2024, 25(7), 3788; https://doi.org/10.3390/ijms25073788 - 28 Mar 2024

Cited by 8 | Viewed by 2406

Abstract

Despite significant progress in modern medicine and pharmacology, damage to the nervous system with various etiologies still poses a challenge to doctors and scientists. Injuries lead to neuroimmunological changes in the central nervous system (CNS), which may result in both secondary damage and the development of tactile and thermal hypersensitivity. In our review, based on the analysis of many experimental and clinical studies, we indicate that the mechanisms occurring both at the level of the brain after direct damage and at the level of the spinal cord after peripheral nerve damage have a common immunological basis. This suggests that there are opportunities for similar pharmacological therapeutic interventions in the damage of various etiologies. Experimental data indicate that after CNS/PNS damage, the levels of 16 among the 28 CC-family chemokines, i.e., CCL1, CCL2, CCL3, CCL4, CCL5, CCL6, CCL7, CCL8, CCL9, CCL11, CCL12, CCL17, CCL19, CCL20, CCL21, and CCL22, increase in the brain and/or spinal cord and have strong proinflammatory and/or pronociceptive effects. According to the available literature data, further investigation is still needed for understanding the role of the remaining chemokines, especially six of them which were found in humans but not in mice/rats, i.e., CCL13, CCL14, CCL15, CCL16, CCL18, and CCL23. Over the past several years, the results of studies in which available pharmacological tools were used indicated that blocking individual receptors, e.g., CCR1 (J113863 and BX513), CCR2 (RS504393, CCX872, INCB3344, and AZ889), CCR3 (SB328437), CCR4 (C021 and AZD-2098), and CCR5 (maraviroc, AZD-5672, and TAK-220), has beneficial effects after damage to both the CNS and PNS. Recently, experimental data have proved that blockades exerted by double antagonists CCR1/3 (UCB 35625) and CCR2/5 (cenicriviroc) have very good anti-inflammatory and antinociceptive effects. In addition, both single (J113863, RS504393, SB328437, C021, and maraviroc) and dual (cenicriviroc) chemokine receptor antagonists enhanced the analgesic effect of opioid drugs. This review will display the evidence that a multidirectional strategy based on the modulation of neuronal–glial–immune interactions can significantly improve the health of patients after CNS and PNS damage by changing the activity of chemokines belonging to the CC family. Moreover, in the case of pain, the combined administration of such antagonists with opioid drugs could reduce therapeutic doses and minimize the risk of complications. Full article

(This article belongs to the Special Issue The Multiple Mechanisms Underlying Neuropathic Pain (III))

► Show Figures

Journal Menu

Journal Browser

The Multiple Mechanisms Underlying Neuropathic Pain (III)

Share This Special Issue

Special Issue Editors

Special Issue Information

Keywords

Benefits of Publishing in a Special Issue

Published Papers (7 papers)

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI