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The Multiple Mechanisms Underlying Neuropathic Pain (II)
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The Multiple Mechanisms Underlying Neuropathic Pain (II)

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 (28 February 2023) | Viewed by 17688

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

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Keywords

  • neuropathic pain
  • nociception
  • neuroinflammation
  • sex differences
  • sex hormones
  • analgesic response

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Published Papers (6 papers)

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Editorial

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4 pages, 199 KiB  
Editorial
A Step Forward: About the Progresses Made in the Second Edition of the Special Issue “The Multiple Mechanisms Underlying Neuropathic Pain”
by Sara Marinelli and Roberto Coccurello
Int. J. Mol. Sci. 2023, 24(10), 8590; https://doi.org/10.3390/ijms24108590 - 11 May 2023
Viewed by 1132
Abstract
The present editorial intends to comment on the contributions published in the second edition of the Special Issue (SI) “The Multiple Mechanisms Underlying Neuropathic Pain” [...] Full article
(This article belongs to the Special Issue The Multiple Mechanisms Underlying Neuropathic Pain (II))

Research

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11 pages, 1346 KiB  
Article
Altered Brain Expression of DNA Methylation and Hydroxymethylation Epigenetic Enzymes in a Rat Model of Neuropathic Pain
by Diogo Rodrigues, Clara Monteiro, Helder Cardoso-Cruz and Vasco Galhardo
Int. J. Mol. Sci. 2023, 24(8), 7305; https://doi.org/10.3390/ijms24087305 - 15 Apr 2023
Cited by 7 | Viewed by 2345
Abstract
The role of epigenetics in chronic pain at the supraspinal level is yet to be fully characterized. DNA histone methylation is crucially regulated by de novo methyltransferases (DNMT1-3) and ten-eleven translocation dioxygenases (TET1-3). Evidence has shown that methylation markers are altered in different [...] Read more.
The role of epigenetics in chronic pain at the supraspinal level is yet to be fully characterized. DNA histone methylation is crucially regulated by de novo methyltransferases (DNMT1-3) and ten-eleven translocation dioxygenases (TET1-3). Evidence has shown that methylation markers are altered in different CNS regions related to nociception, namely the dorsal root ganglia, the spinal cord, and different brain areas. Decreased global methylation was found in the DRG, the prefrontal cortex, and the amygdala, which was associated with decreased DNMT1/3a expression. In contrast, increased methylation levels and mRNA levels of TET1 and TET3 were linked to augmented pain hypersensitivity and allodynia in inflammatory and neuropathic pain models. Since epigenetic mechanisms may be responsible for the regulation and coordination of various transcriptional modifications described in chronic pain states, with this study, we aimed to evaluate the functional role of TET1-3 and DNMT1/3a genes in neuropathic pain in several brain areas. In a spared nerve injury rat model of neuropathic pain, 21 days after surgery, we found increased TET1 expression in the medial prefrontal cortex and decreased expression in the caudate-putamen and the amygdala; TET2 was upregulated in the medial thalamus; TET3 mRNA levels were reduced in the medial prefrontal cortex and the caudate-putamen; and DNMT1 was downregulated in the caudate-putamen and the medial thalamus. No statistically significant changes in expression were observed with DNMT3a. Our results suggest a complex functional role for these genes in different brain areas in the context of neuropathic pain. The notion of DNA methylation and hydroxymethylation being cell-type specific and not tissue specific, as well as the possibility of chronologically differential gene expression after the establishment of neuropathic or inflammatory pain models, ought to be addressed in future studies. Full article
(This article belongs to the Special Issue The Multiple Mechanisms Underlying Neuropathic Pain (II))
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11 pages, 1308 KiB  
Communication
Impaired Pain Processing at a Brainstem Level Is Involved in Maladaptive Neuroplasticity in Patients with Chronic Complex Regional Pain Syndrome
by Pauline Thoma, Nina Drämel, Matthias Grothe, Martin Lotze, Robert Fleischmann and Sebastian Strauss
Int. J. Mol. Sci. 2022, 23(23), 15368; https://doi.org/10.3390/ijms232315368 - 6 Dec 2022
Cited by 2 | Viewed by 1874
Abstract
Neuroinflammatory mechanisms and maladaptive neuroplasticity underlie the progression of complex regional pain syndrome (CRPS), which is prototypical of central neuropathic pain conditions. While cortical maladaptive alterations are well described, little is known about the contribution of the brainstem to the pathophysiology. This study [...] Read more.
Neuroinflammatory mechanisms and maladaptive neuroplasticity underlie the progression of complex regional pain syndrome (CRPS), which is prototypical of central neuropathic pain conditions. While cortical maladaptive alterations are well described, little is known about the contribution of the brainstem to the pathophysiology. This study investigates the role of pain-modulatory brainstem pathways in CRPS using the nociceptive blink reflex (nBR), which not only provides a direct read-out of brainstem excitability and habituation to painful stimuli but may also be suitable for use as a diagnostic biomarker for CRPS. Thirteen patients with CRPS and thirteen healthy controls (HCs) participated in this prospective case-control study investigating the polysynaptic trigemino-cervical (R2) nBR response. The R2 area and its habituation were assessed following repeated supraorbital electrical stimulation. Between-group comparisons included evaluations of diagnostic characteristics as a potential biomarker for the disease. Patients with CRPS showed a substantial decrease in habituation on the stimulated (Cohen’s d: 1.3; p = 0.012) and the non-stimulated side (Cohen’s d: 1.1; p = 0.04). This is the first study to reveal altered nBR habituation as a pathophysiological mechanism and potential diagnostic biomarker in CRPS. We confirmed previous findings of altered nBR excitability, but the diagnostic accuracy was inferior. Future studies should investigate the nBR as a marker of progression to central mechanisms in CRPS and as a biomarker to predict treatment response or prognosis. Full article
(This article belongs to the Special Issue The Multiple Mechanisms Underlying Neuropathic Pain (II))
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22 pages, 3808 KiB  
Article
Sex Differences in Neuropathy: The Paradigmatic Case of MetFormin
by Federica De Angelis, Valentina Vacca, Jessica Tofanicchio, Georgios Strimpakos, Giacomo Giacovazzo, Flaminia Pavone, Roberto Coccurello and Sara Marinelli
Int. J. Mol. Sci. 2022, 23(23), 14503; https://doi.org/10.3390/ijms232314503 - 22 Nov 2022
Cited by 10 | Viewed by 2279
Abstract
As a widely prescribed anti-diabetic drug, metformin has been receiving novel attention for its analgesic potential. In the study of the complex etiology of neuropathic pain (NeP), male and female individuals exhibit quite different responses characterized by higher pain sensitivity and greater NeP [...] Read more.
As a widely prescribed anti-diabetic drug, metformin has been receiving novel attention for its analgesic potential. In the study of the complex etiology of neuropathic pain (NeP), male and female individuals exhibit quite different responses characterized by higher pain sensitivity and greater NeP incidence in women. This “gender gap” in our knowledge of sex differences in pain processing strongly limits the sex-oriented treatment of patients suffering from NeP. Besides, the current investigation of the analgesic potential of metformin has not addressed the “gender gap” problem. Hence, this study focuses on metformin and sex-dependent analgesia in a murine model of NeP induced by chronic constriction injury of the sciatic nerve. We investigated sexual dimorphism in signaling pathways involved by 7 days of metformin administration, such as changes in AMP-activated protein kinase and the positive regulation of autophagy machinery, discovering that metformin affected in a sexually dimorphic manner the immunological and inflammatory response to nerve lesion. These effects were complemented by morphological and adaptive changes occurring after peripheral nerve injury. Altogether these data can contribute to explaining a number of potential mechanisms responsible for the complete recovery from NeP found in male mice, as opposed to the failure of long-lasting recovery in female animals. Full article
(This article belongs to the Special Issue The Multiple Mechanisms Underlying Neuropathic Pain (II))
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16 pages, 7547 KiB  
Article
Mu and Delta Opioid Receptor Targeting Reduces Connexin 43-Based Heterocellular Coupling during Neuropathic Pain
by Nunzio Vicario, Simona Denaro, Rita Turnaturi, Lucia Longhitano, Federica Maria Spitale, Salvatore Spoto, Agostino Marrazzo, Agata Zappalà, Daniele Tibullo, Giovanni Li Volti, Santina Chiechio, Lorella Pasquinucci, Rosalba Parenti and Carmela Parenti
Int. J. Mol. Sci. 2022, 23(11), 5864; https://doi.org/10.3390/ijms23115864 - 24 May 2022
Cited by 14 | Viewed by 2447
Abstract
Chronic neuropathic pain emerges from either central or peripheral lesions inducing spontaneous or amplified responses to non-noxious stimuli. Despite different pharmacological approaches to treat such a chronic disease, neuropathic pain still represents an unmet clinical need, due to long-term therapeutic regimens and severe [...] Read more.
Chronic neuropathic pain emerges from either central or peripheral lesions inducing spontaneous or amplified responses to non-noxious stimuli. Despite different pharmacological approaches to treat such a chronic disease, neuropathic pain still represents an unmet clinical need, due to long-term therapeutic regimens and severe side effects that limit application of currently available drugs. A critical phenomenon involved in central sensitization is the exchange of signalling molecules and cytokines, between glia and neurons, driving the chronicization process. Herein, using a chronic constriction injury (CCI) model of neuropathic pain, we evaluated the efficacy of the mu (M-) and delta (D-) opioid receptor (-OR) targeting agent LP2 in modulating connexin-based heterocellular coupling and cytokine levels. We found that long-term efficacy of LP2 is consequent to MOR-DOR targeting resulting in the reduction of CCI-induced astrocyte-to-microglia heterocellular coupling mediated by connexin 43. We also found that single targeting of DOR reduces TNF and IL-6 levels in the chronic phase of the disease, but the peripheral and central discharge as the primary source of excitotoxic stimulation in the spinal cord requires a simultaneous MOR-DOR targeting to reduce CCI-induced neuropathic pain. Full article
(This article belongs to the Special Issue The Multiple Mechanisms Underlying Neuropathic Pain (II))
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Review

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16 pages, 686 KiB  
Review
The Role of the Insular Cortex in Pain
by Charalampos Labrakakis
Int. J. Mol. Sci. 2023, 24(6), 5736; https://doi.org/10.3390/ijms24065736 - 17 Mar 2023
Cited by 49 | Viewed by 6672
Abstract
The transition from normal to chronic pain is believed to involve alterations in several brain areas that participate in the perception of pain. These plastic changes are then responsible for aberrant pain perception and comorbidities. The insular cortex is consistently found activated in [...] Read more.
The transition from normal to chronic pain is believed to involve alterations in several brain areas that participate in the perception of pain. These plastic changes are then responsible for aberrant pain perception and comorbidities. The insular cortex is consistently found activated in pain studies of normal and chronic pain patients. Functional changes in the insula contribute to chronic pain; however, the complex mechanisms by which the insula is involved in pain perception under normal and pathological conditions are still not clear. In this review, an overview of the insular function is provided and findings on its role in pain from human studies are summarized. Recent progress on the role of the insula in pain from preclinical experimental models is reviewed, and the connectivity of the insula with other brain regions is examined to shed new light on the neuronal mechanisms of the insular cortex’s contribution to normal and pathological pain sensation. This review underlines the need for further studies on the mechanisms underlying the involvement of the insula in the chronicity of pain and the expression of comorbid disorders. Full article
(This article belongs to the Special Issue The Multiple Mechanisms Underlying Neuropathic Pain (II))
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