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The Multiple Mechanisms Underlying Neuropathic Pain
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The Multiple Mechanisms Underlying Neuropathic Pain

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 (15 January 2021) | Viewed by 21526

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 defense of the body’s integrity and persistent pain as 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 towards 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. Despite several factors (e.g., genetic, hormonal, physiological and neuronal) 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 the 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 the neuroinflammatory aspects and sexual dimorphism in response to pain killers. 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.

Prof. 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

Published Papers (6 papers)

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Editorial

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3 pages, 203 KiB  
Editorial
From the Gender Gap to Neuroactive Steroids: Exploring Multiple Cases to Further Understand Neuropathic Pain
by Sara Marinelli and Roberto Coccurello
Int. J. Mol. Sci. 2023, 24(10), 8577; https://doi.org/10.3390/ijms24108577 - 11 May 2023
Cited by 2 | Viewed by 987
Abstract
Neuropathic pain (NeuP) is still an intractable form of highly debilitating chronic pain, resulting from a lesion or disease of the somatosensory nervous system [...] Full article
(This article belongs to the Special Issue The Multiple Mechanisms Underlying Neuropathic Pain)

Research

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22 pages, 5306 KiB  
Article
Sexually Dimorphic Immune and Neuroimmune Changes Following Peripheral Nerve Injury in Mice: Novel Insights for Gender Medicine
by Valentina Vacca, Sara Marinelli, Federica De Angelis, Daniela F. Angelini, Eleonora Piras, Luca Battistini, Flaminia Pavone and Roberto Coccurello
Int. J. Mol. Sci. 2021, 22(9), 4397; https://doi.org/10.3390/ijms22094397 - 22 Apr 2021
Cited by 16 | Viewed by 2561
Abstract
Neuropathic pain (NeP) in humans is often a life-long condition with no effective therapy available. The higher incidence of female gender in NeP onset is worldwide reported, and although the cause is generally attributed to sex hormones, the actual mechanisms and the players [...] Read more.
Neuropathic pain (NeP) in humans is often a life-long condition with no effective therapy available. The higher incidence of female gender in NeP onset is worldwide reported, and although the cause is generally attributed to sex hormones, the actual mechanisms and the players involved are still unclear. Glial and immune cells take part in NeP development, and orchestrate the neuroimmune and inflammatory response, releasing pro-inflammatory factors with chemoattractant properties that activate resident immune cells and recruit immune cells from circulation. The neuro-immune crosstalk is a key contributor to pain hypersensitivity following peripheral nervous system injury. Our previous works showed that in spite of the fact that female mice had an earlier analgesic response than males following nerve lesion, the recovery from NeP was never complete, suggesting that this difference could occur in the very early stages after injury. To further investigate gender differences in immune and neuroimmune responses to NeP, we studied the main immune cells and mediators elicited both in plasma and sciatic nerves by peripheral nerve lesion. After injury, we found a different pattern of distribution of immune cell populations showing either a higher infiltration of T cells in nerves from females or a higher infiltration of macrophages in nerves from males. Moreover, in comparison to male mice, the levels of cytokines and chemokines were differently up- and down-regulated in blood and nerve lysates from female mice. Our study provides some novel insights for the understanding of gender-associated differences in the generation and perseveration of NeP as well as for the isolation of specific neurodegenerative mechanisms underlying NeP. The identification of gender-associated inflammatory profiles in neuropathy is of key importance for the development of differential biomarkers and gender-specific personalized medicine. Full article
(This article belongs to the Special Issue The Multiple Mechanisms Underlying Neuropathic Pain)
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24 pages, 15917 KiB  
Article
Cross-Talk of Toll-Like Receptor 5 and Mu-Opioid Receptor Attenuates Chronic Constriction Injury-Induced Mechanical Hyperalgesia through a Protein Kinase C Alpha-Dependent Signaling
by Ching Chang, Hung-Kai Liu, Chao-Bin Yeh, Ming-Lin Yang, Wen-Chieh Liao, Chiung-Hui Liu and To-Jung Tseng
Int. J. Mol. Sci. 2021, 22(4), 1891; https://doi.org/10.3390/ijms22041891 - 14 Feb 2021
Cited by 5 | Viewed by 3218
Abstract
Recently, Toll-like receptors (TLRs), a family of pattern recognition receptors, are reported as potential modulators for neuropathic pain; however, the desired mechanism is still unexplained. Here, we operated on the sciatic nerve to establish a pre-clinical rodent model of chronic constriction injury (CCI) [...] Read more.
Recently, Toll-like receptors (TLRs), a family of pattern recognition receptors, are reported as potential modulators for neuropathic pain; however, the desired mechanism is still unexplained. Here, we operated on the sciatic nerve to establish a pre-clinical rodent model of chronic constriction injury (CCI) in Sprague-Dawley rats, which were assigned into CCI and Decompression groups randomly. In Decompression group, the rats were performed with nerve decompression at post-operative week 4. Mechanical hyperalgesia and mechanical allodynia were obviously attenuated after a month. Toll-like receptor 5 (TLR5)-immunoreactive (ir) expression increased in dorsal horn, particularly in the inner part of lamina II. Additionally, substance P (SP) and isolectin B4 (IB4)-ir expressions, rather than calcitonin-gene-related peptide (CGRP)-ir expression, increased in their distinct laminae. Double immunofluorescence proved that increased TLR5-ir expression was co-expressed mainly with IB4-ir expression. Through an intrathecal administration with FLA-ST Ultrapure (a TLR5 agonist, purified flagellin from Salmonella Typhimurium, only the CCI-induced mechanical hyperalgesia was attenuated dose-dependently. Moreover, we confirmed that mu-opioid receptor (MOR) and phospho-protein kinase Cα (pPKCα)-ir expressions but not phospho-protein kinase A RII (pPKA RII)-ir expression, increased in lamina II, where they mostly co-expressed with IB4-ir expression. Go 6976, a potent protein kinase C inhibitor, effectively reversed the FLA-ST Ultrapure- or DAMGO-mediated attenuated trend towards mechanical hyperalgesia by an intrathecal administration in CCI rats. In summary, our current findings suggest that nerve decompression improves CCI-induced mechanical hyperalgesia that might be through the cross-talk of TLR5 and MOR in a PKCα-dependent manner, which opens a novel opportunity for the development of analgesic therapeutics in neuropathic pain. Full article
(This article belongs to the Special Issue The Multiple Mechanisms Underlying Neuropathic Pain)
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Review

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36 pages, 2535 KiB  
Review
Effects of Curcumin and Its Different Formulations in Preclinical and Clinical Studies of Peripheral Neuropathic and Postoperative Pain: A Comprehensive Review
by Paramita Basu, Camelia Maier and Arpita Basu
Int. J. Mol. Sci. 2021, 22(9), 4666; https://doi.org/10.3390/ijms22094666 - 28 Apr 2021
Cited by 21 | Viewed by 6819
Abstract
Lesion or disease of the somatosensory system leads to the development of neuropathic pain. Peripheral neuropathic pain encompasses damage or injury of the peripheral nervous system. On the other hand, 10–15% of individuals suffer from acute postoperative pain followed by persistent pain after [...] Read more.
Lesion or disease of the somatosensory system leads to the development of neuropathic pain. Peripheral neuropathic pain encompasses damage or injury of the peripheral nervous system. On the other hand, 10–15% of individuals suffer from acute postoperative pain followed by persistent pain after undergoing surgeries. Antidepressants, anticonvulsants, baclofen, and clonidine are used to treat peripheral neuropathy, whereas opioids are used to treat postoperative pain. The negative effects associated with these drugs emphasize the search for alternative therapeutics with better efficacy and fewer side effects. Curcumin, a polyphenol isolated from the roots of Curcuma longa, possesses antibacterial, antioxidant, and anti-inflammatory properties. Furthermore, the low bioavailability and fast metabolism of curcumin have led to the advent of various curcumin formulations. The present review provides a comprehensive analysis on the effects of curcumin and its formulations in preclinical and clinical studies of neuropathic and postoperative pain. Based on the positive outcomes from both preclinical and clinical studies, curcumin holds the promise of mitigating or preventing neuropathic and postoperative pain conditions. However, more clinical studies with improved curcumin formulations are required to involve its use as adjuvant to neuropathic and postoperative drugs. Full article
(This article belongs to the Special Issue The Multiple Mechanisms Underlying Neuropathic Pain)
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16 pages, 767 KiB  
Review
Current Understanding of the Involvement of the Insular Cortex in Neuropathic Pain: A Narrative Review
by Ning Wang, Yu-Han Zhang, Jin-Yan Wang and Fei Luo
Int. J. Mol. Sci. 2021, 22(5), 2648; https://doi.org/10.3390/ijms22052648 - 5 Mar 2021
Cited by 16 | Viewed by 3367
Abstract
Neuropathic pain is difficult to cure and is often accompanied by emotional and psychological changes. Exploring the mechanisms underlying neuropathic pain will help to identify a better treatment for this condition. The insular cortex is an important information integration center. Numerous imaging studies [...] Read more.
Neuropathic pain is difficult to cure and is often accompanied by emotional and psychological changes. Exploring the mechanisms underlying neuropathic pain will help to identify a better treatment for this condition. The insular cortex is an important information integration center. Numerous imaging studies have documented increased activity of the insular cortex in the presence of neuropathic pain; however, the specific role of this region remains controversial. Early studies suggested that the insular lobe is mainly involved in the processing of the emotional motivation dimension of pain. However, increasing evidence suggests that the role of the insular cortex is more complex and may even be related to the neural plasticity, cognitive evaluation, and psychosocial aspects of neuropathic pain. These effects contribute not only to the development of neuropathic pain, but also to its comorbidity with neuropsychiatric diseases. In this review, we summarize the changes that occur in the insular cortex in the presence of neuropathic pain and analgesia, as well as the molecular mechanisms that may underlie these conditions. We also discuss potential sex-based differences in these processes. Further exploration of the involvement of the insular lobe will contribute to the development of new pharmacotherapy and psychotherapy treatments for neuropathic pain. Full article
(This article belongs to the Special Issue The Multiple Mechanisms Underlying Neuropathic Pain)
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25 pages, 1565 KiB  
Review
Physiopathological Role of Neuroactive Steroids in the Peripheral Nervous System
by Eva Falvo, Silvia Diviccaro, Roberto Cosimo Melcangi and Silvia Giatti
Int. J. Mol. Sci. 2020, 21(23), 9000; https://doi.org/10.3390/ijms21239000 - 26 Nov 2020
Cited by 15 | Viewed by 3749
Abstract
Peripheral neuropathy (PN) refers to many conditions involving damage to the peripheral nervous system (PNS). Usually, PN causes weakness, numbness and pain and is the result of traumatic injuries, infections, metabolic problems, inherited causes, or exposure to chemicals. Despite the high prevalence of [...] Read more.
Peripheral neuropathy (PN) refers to many conditions involving damage to the peripheral nervous system (PNS). Usually, PN causes weakness, numbness and pain and is the result of traumatic injuries, infections, metabolic problems, inherited causes, or exposure to chemicals. Despite the high prevalence of PN, available treatments are still unsatisfactory. Neuroactive steroids (i.e., steroid hormones synthesized by peripheral glands as well as steroids directly synthesized in the nervous system) represent important physiological regulators of PNS functionality. Data obtained so far and here discussed, indeed show that in several experimental models of PN the levels of neuroactive steroids are affected by the pathology and that treatment with these molecules is able to exert protective effects on several PN features, including neuropathic pain. Of note, the observations that neuroactive steroid levels are sexually dimorphic not only in physiological status but also in PN, associated with the finding that PN show sex dimorphic manifestations, may suggest the possibility of a sex specific therapy based on neuroactive steroids. Full article
(This article belongs to the Special Issue The Multiple Mechanisms Underlying Neuropathic Pain)
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