International Journal of Molecular Sciences

Editorial

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3 pages, 197 KiB

Open AccessEditorial

Molecular Links between Sensory Nerves, Inflammation, and Pain 2.0

by Éva Szőke and Zsuzsanna Helyes

Int. J. Mol. Sci. 2023, 24(15), 12243; https://doi.org/10.3390/ijms241512243 - 31 Jul 2023

Cited by 1 | Viewed by 1063

Abstract

Capsaicin-sensitive peptidergic sensory nerves mediate triple actions: besides transmitting sensory and pain signals to the central nervous system (afferent function), they also have local and systemic efferent functions [...] Full article

(This article belongs to the Special Issue Molecular Links between Sensory Nerves, Inflammation, and Pain 2.0)

Research

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25 pages, 6031 KiB

Open AccessArticle

IL-1 Mediates Chronic Stress-Induced Hyperalgesia Accompanied by Microglia and Astroglia Morphological Changes in Pain-Related Brain Regions in Mice

by Barbara Fülöp, Ágnes Hunyady, Noémi Bencze, Viktória Kormos, Nikolett Szentes, Ádám Dénes, Nikolett Lénárt, Éva Borbély and Zsuzsanna Helyes

Int. J. Mol. Sci. 2023, 24(6), 5479; https://doi.org/10.3390/ijms24065479 - 13 Mar 2023

Cited by 10 | Viewed by 3647

Abstract

Chronic stress causes several pain conditions including fibromyalgia. Its pathophysiological mechanisms are unknown, and the therapy is unresolved. Since the involvement of interleukin-1 (IL-1) has been described in stress and inflammatory pain but no data are available regarding stress-induced pain, we studied its [...] Read more.

Chronic stress causes several pain conditions including fibromyalgia. Its pathophysiological mechanisms are unknown, and the therapy is unresolved. Since the involvement of interleukin-1 (IL-1) has been described in stress and inflammatory pain but no data are available regarding stress-induced pain, we studied its role in a chronic restraint stress (CRS) mouse model. Female and male C57Bl/6J wild-type (WT) and IL-1αβ-deficient (knock-out: IL-1 KO) mice were exposed to 6 h of immobilization/day for 4 weeks. Mechanonociception, cold tolerance, behavioral alterations, relative thymus/adrenal gland weights, microglia ionized calcium-binding adaptor molecule 1 (IBA1) and astrocyte glial fibrillary acidic protein (GFAP) integrated density, number and morphological transformation in pain-related brain regions were determined. CRS induced 15–20% mechanical hyperalgesia after 2 weeks in WT mice in both sexes, which was significantly reduced in female but not in male IL-1 KOs. Increased IBA1+ integrated density in the central nucleus of amygdala, primary somatosensory cortex hind limb representation part, hippocampus cornu ammonis area 3 (CA3) and periaqueductal gray matter (PAG) was present, accompanied by a cell number increase in IBA1+ microglia in stressed female WTs but not in IL-1 KOs. CRS induced morphological changes of GFAP+ astrocytes in WT but not in KO mice. Stress evoked cold hypersensitivity in the stressed animals. Anxiety and depression-like behaviors, thymus and adrenal gland weight changes were detectable in all groups after 2 but not 4 weeks of CRS due to adaptation. Thus, IL-1 mediates chronic stress-induced hyperalgesia in female mice, without other major behavioral alterations, suggesting the analgesic potentials of IL-1 in blocking drugs in stress-related pain syndromes. Full article

(This article belongs to the Special Issue Molecular Links between Sensory Nerves, Inflammation, and Pain 2.0)

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25 pages, 3275 KiB

Open AccessArticle

Unique, Specific CART Receptor-Independent Regulatory Mechanism of CART(55-102) Peptide in Spinal Nociceptive Transmission and Its Relation to Dipeptidyl-Peptidase 4 (DDP4)

by Márk Kozsurek, Kornél Király, Klára Gyimesi, Erika Lukácsi, Csaba Fekete, Balázs Gereben, Petra Mohácsik, Zsuzsanna Helyes, Kata Bölcskei, Valéria Tékus, Károly Pap, Edina Szűcs, Sándor Benyhe, Tímea Imre, Pál Szabó, Andrea Gajtkó, Krisztina Holló and Zita Puskár

Int. J. Mol. Sci. 2023, 24(2), 918; https://doi.org/10.3390/ijms24020918 - 4 Jan 2023

Cited by 2 | Viewed by 3350

Abstract

Cocaine- and amphetamine-regulated transcript (CART) peptides are involved in several physiological and pathological processes, but their mechanism of action is unrevealed due to the lack of identified receptor(s). We provided evidence for the antihyperalgesic effect of CART(55-102) by inhibiting dipeptidyl-peptidase 4 (DPP4) in [...] Read more.

Cocaine- and amphetamine-regulated transcript (CART) peptides are involved in several physiological and pathological processes, but their mechanism of action is unrevealed due to the lack of identified receptor(s). We provided evidence for the antihyperalgesic effect of CART(55-102) by inhibiting dipeptidyl-peptidase 4 (DPP4) in astrocytes and consequently reducing neuroinflammation in the rat spinal dorsal horn in a carrageenan-evoked inflammation model. Both naturally occurring CART(55-102) and CART(62-102) peptides are present in the spinal cord. CART(55-102) is not involved in acute nociception but regulates spinal pain transmission during peripheral inflammation. While the full-length peptide with a globular motif contributes to hyperalgesia, its N-terminal inhibits this process. Although the anti-hyperalgesic effects of CART(55-102), CART(55-76), and CART(62-76) are blocked by opioid receptor antagonists in our inflammatory models, but not in neuropathic Seltzer model, none of them bind to any opioid or G-protein coupled receptors. DPP4 interacts with Toll-like receptor 4 (TLR4) signalling in spinal astrocytes and enhances the TLR4-induced expression of interleukin-6 and tumour necrosis factor alpha contributing to inflammatory pain. Depending on the state of inflammation, CART(55-102) is processed in the spinal cord, resulting in the generation of biologically active isoleucine-proline-isoleucine (IPI) tripeptide, which inhibits DPP4, leading to significantly decreased glia-derived cytokine production and hyperalgesia. Full article

(This article belongs to the Special Issue Molecular Links between Sensory Nerves, Inflammation, and Pain 2.0)

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17 pages, 4187 KiB

Open AccessArticle

Silencing P2X7R Alleviates Diabetic Neuropathic Pain Involving TRPV1 via PKCε/P38MAPK/NF-κB Signaling Pathway in Rats

by Lisha Chen, Hongji Wang, Juping Xing, Xiangchao Shi, Huan Huang, Jiabao Huang and Changshui Xu

Int. J. Mol. Sci. 2022, 23(22), 14141; https://doi.org/10.3390/ijms232214141 - 16 Nov 2022

Cited by 20 | Viewed by 2632

Abstract

Transient receptor potential vanillic acid 1 (TRPV1) is an ion channel activated by heat and inflammatory factors involved in the development of various types of pain. The P2X7 receptor is in the P2X family and is associated with pain mediated by satellite glial [...] Read more.

Transient receptor potential vanillic acid 1 (TRPV1) is an ion channel activated by heat and inflammatory factors involved in the development of various types of pain. The P2X7 receptor is in the P2X family and is associated with pain mediated by satellite glial cells. There might be some connection between the P2X7 receptor and TRPV1 in neuropathic pain in diabetic rats. A type 2 diabetic neuropathic pain rat model was induced using high glucose and high-fat diet for 4 weeks and low-dose streptozocin (35 mg/kg) intraperitoneal injection to destroy islet B cells. Male Sprague Dawley rats were administrated by intrathecal injection of P2X7 shRNA and p38 inhibitor, and we recorded abnormal mechanical and thermal pain and nociceptive hyperalgesia. One week later, the dorsal root ganglia from the L4-L6 segment of the spinal cord were harvested for subsequent experiments. We measured pro-inflammatory cytokines, examined the relationship between TRPV1 on neurons and P2X7 receptor on satellite glial cells by measuring protein and transcription levels of P2X7 receptor and TRPV1, and measured protein expression in the PKCε/P38 MAPK/NF-κB signaling pathway after intrathecal injection. P2X7 shRNA and p38 inhibitor relieved hyperalgesia in diabetic neuropathic pain rats and modulated inflammatory factors in vivo. P2X7 shRNA and P38 inhibitors significantly reduced TRPV1 expression by downregulating the PKCε/P38 MAPK/NF-κB signaling pathway and inflammatory factors in dorsal root ganglia. Intrathecal injection of P2X7 shRNA alleviates nociceptive reactions in rats with diabetic neuropathic pain involving TRPV1 via PKCε/P38 MAPK/NF-κB signaling pathway. Full article

(This article belongs to the Special Issue Molecular Links between Sensory Nerves, Inflammation, and Pain 2.0)

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17 pages, 2241 KiB

Open AccessArticle

Elucidating the Ability of CGRP to Modulate Microvascular Events in Mouse Skin

by Ali A. Zarban, Hiba Chaudhry, João de Sousa Valente, Fulye Argunhan, Hala Ghanim and Susan D. Brain

Int. J. Mol. Sci. 2022, 23(20), 12246; https://doi.org/10.3390/ijms232012246 - 13 Oct 2022

Cited by 4 | Viewed by 3014

Abstract

Oedema formation and polymorphonuclear leukocyte (neutrophil) accumulation are involved in both acute and chronic inflammation. Calcitonin gene-related peptide (CGRP) is a sensory neuropeptide that is released from stimulated sensory nerves. CGRP is a potent vasodilator neuropeptide, especially when administered to the cutaneous microvasculature, [...] Read more.

Oedema formation and polymorphonuclear leukocyte (neutrophil) accumulation are involved in both acute and chronic inflammation. Calcitonin gene-related peptide (CGRP) is a sensory neuropeptide that is released from stimulated sensory nerves. CGRP is a potent vasodilator neuropeptide, especially when administered to the cutaneous microvasculature, with a long duration of action. Here, we have investigated the ability of vasodilator amounts of CGRP to modulate oedema formation and neutrophil accumulation induced in the cutaneous microvasculature of the mouse. To learn more about the mechanism of action of endogenous CGRP, we have investigated the response to the inflammatory stimulants tumour necrosis factor alpha (TNFα) and carrageenan in three different murine models: a model where sensory nerves were depleted by resiniferatoxin (RTX); a pharmacological method to investigate the effect of a selective CGRP receptor antagonist; and a genetic approach using wildtype (WT) and αCGRP knockout (KO) mice. Our results show that exogenous CGRP potentiates oedema formation induced by substance P (SP) and TNFα. This is further supported by our findings from sensory nerve-depleted mice (in the absence of all neuropeptides), which indicated that sensory nerves are involved in mediating the oedema formation and neutrophil accumulation induced by TNFα, and also carrageenan in cutaneous microvasculature. Furthermore, endogenous CGRP was shown to contribute to this inflammatory response as carrageenan-induced oedema formation is attenuated in WT mice treated with the CGRP receptor antagonist, and in αCGRPKO mice. It is therefore concluded that CGRP can contribute to inflammation by promoting oedema formation in skin, but this response is dependent on the pro-inflammatory stimulus and circumstance. Full article

(This article belongs to the Special Issue Molecular Links between Sensory Nerves, Inflammation, and Pain 2.0)

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13 pages, 1918 KiB

Open AccessArticle

The Acute Antiallodynic Effect of Tolperisone in Rat Neuropathic Pain and Evaluation of Its Mechanism of Action

by Péter P. Lakatos, Dávid Árpád Karádi, Anna Rita Galambos, Nariman Essmat, Kornél Király, Rudolf Laufer, Orsolya Geda, Zoltán S. Zádori, Tamás Tábi, Mahmoud Al-Khrasani and Éva Szökő

Int. J. Mol. Sci. 2022, 23(17), 9564; https://doi.org/10.3390/ijms23179564 - 24 Aug 2022

Cited by 5 | Viewed by 2324

Abstract

Current treatment approaches to manage neuropathic pain have a slow onset and their use is largely hampered by side-effects, thus there is a significant need for finding new medications. Tolperisone, a centrally acting muscle relaxant with a favorable side effect profile, has been [...] Read more.

Current treatment approaches to manage neuropathic pain have a slow onset and their use is largely hampered by side-effects, thus there is a significant need for finding new medications. Tolperisone, a centrally acting muscle relaxant with a favorable side effect profile, has been reported to affect ion channels, which are targets for current first-line medications in neuropathic pain. Our aim was to explore its antinociceptive potency in rats developing neuropathic pain evoked by partial sciatic nerve ligation and the mechanisms involved. Acute oral tolperisone restores both the decreased paw pressure threshold and the elevated glutamate level in cerebrospinal fluid in neuropathic rats. These effects were comparable to those of pregabalin, a first-line medication in neuropathy. Tolperisone also inhibits release of glutamate from rat brain synaptosomes primarily by blockade of voltage-dependent sodium channels, although inhibition of calcium channels may also be involved at higher concentrations. However, pregabalin fails to affect glutamate release under our present conditions, indicating a different mechanism of action. These results lay the foundation of the avenue for repurposing tolperisone as an analgesic drug to relieve neuropathic pain. Full article

(This article belongs to the Special Issue Molecular Links between Sensory Nerves, Inflammation, and Pain 2.0)

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15 pages, 2500 KiB

Open AccessArticle

Investigation of the Role of Pituitary Adenylate Cyclase-Activating Peptide (PACAP) and Its Type 1 (PAC1) Receptor in Uterine Contractility during Endometritis in Pigs

by Barbara Jana, Jarosław Całka and Krzysztof Witek

Int. J. Mol. Sci. 2022, 23(10), 5467; https://doi.org/10.3390/ijms23105467 - 13 May 2022

Cited by 2 | Viewed by 1949

Abstract

Uterine inflammation is a common pathology in animals, leading to disturbances in reproductive processes and reduced production profitability. Pituitary adenylate cyclase-activating peptide (PACAP) effects at the uterine level during inflammation are not known. In the current study, we analyzed the relative PACAP type [...] Read more.

Uterine inflammation is a common pathology in animals, leading to disturbances in reproductive processes and reduced production profitability. Pituitary adenylate cyclase-activating peptide (PACAP) effects at the uterine level during inflammation are not known. In the current study, we analyzed the relative PACAP type 1 receptor (PAC1R) mRNA transcript and protein abundances in the myometrium (MYO), as well s PACAP and PAC1R involvement in the contractile function of inflamed pig uterus. To that end, E. coli suspension (E. coli group) or saline (SAL group) was injected into the uterine horns or laparotomy was performed (CON group). Eight days after the bacteria injections, severe acute endometritis and a reduced relative abundance of PAC1R protein in the MYO were observed. Compared to the period before PACAP in vitro administration, PACAP (10⁻⁷ M) in the CON and SAL groups decreased in amplitude in the MYO and endometrium (ENDO)/MYO, whereas in the E. coli group, increased amplitude in the MYO and reduced amplitude in the ENDO/MYO were observed. In the E. coli group, PACAP enhanced the amplitude in the MYO (10⁻⁷ M) and decreased the amplitude in the ENDO/MYO (10⁻⁸ M) compared with other groups. PACAP (10⁻⁷ M) increased the frequency of both kinds of strips in the CON and SAL groups compared with the pretreatment period. PACAP (both doses) did not significantly change the frequency in the E. coli group, whereas in response to PACAP (10⁻⁷ M), the frequency was reduced compared to other groups. In the MYO, PAC1R antagonist decreased the amplitude reduction (CON and SAL groups) and reversed a rise in PACAP (10⁻⁷ M)-evoked amplitude (E. coli group). PAC1R blocking reversed (MYO) and abolished (ENDO/MYO) the stimulatory effect of PACAP (10⁻⁷ M) on the frequency (CON and SAL groups). PAC1R antagonist and PACAP (10⁻⁷ M) evoked the appearance of frequency depression in both kinds of strips (E. coli group). In summary, in pigs, severe acute endometritis reduces the relative abundance of PAC1R protein in the MYO, and PAC1R mediates the influence of PACAP on inflamed uterus contractility. Full article

(This article belongs to the Special Issue Molecular Links between Sensory Nerves, Inflammation, and Pain 2.0)

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21 pages, 1711 KiB

Open AccessArticle

Machine Learning and Pathway Analysis-Based Discovery of Metabolomic Markers Relating to Chronic Pain Phenotypes

by Teemu Miettinen, Anni I. Nieminen, Pekka Mäntyselkä, Eija Kalso and Jörn Lötsch

Int. J. Mol. Sci. 2022, 23(9), 5085; https://doi.org/10.3390/ijms23095085 - 3 May 2022

Cited by 10 | Viewed by 3078

Abstract

Recent scientific evidence suggests that chronic pain phenotypes are reflected in metabolomic changes. However, problems associated with chronic pain, such as sleep disorders or obesity, may complicate the metabolome pattern. Such a complex phenotype was investigated to identify common metabolomics markers at the [...] Read more.

Recent scientific evidence suggests that chronic pain phenotypes are reflected in metabolomic changes. However, problems associated with chronic pain, such as sleep disorders or obesity, may complicate the metabolome pattern. Such a complex phenotype was investigated to identify common metabolomics markers at the interface of persistent pain, sleep, and obesity in 71 men and 122 women undergoing tertiary pain care. They were examined for patterns in d = 97 metabolomic markers that segregated patients with a relatively benign pain phenotype (low and little bothersome pain) from those with more severe clinical symptoms (high pain intensity, more bothersome pain, and co-occurring problems such as sleep disturbance). Two independent lines of data analysis were pursued. First, a data-driven supervised machine learning-based approach was used to identify the most informative metabolic markers for complex phenotype assignment. This pointed primarily at adenosine monophosphate (AMP), asparagine, deoxycytidine, glucuronic acid, and propionylcarnitine, and secondarily at cysteine and nicotinamide adenine dinucleotide (NAD) as informative for assigning patients to clinical pain phenotypes. After this, a hypothesis-driven analysis of metabolic pathways was performed, including sleep and obesity. In both the first and second line of analysis, three metabolic markers (NAD, AMP, and cysteine) were found to be relevant, including metabolic pathway analysis in obesity, associated with changes in amino acid metabolism, and sleep problems, associated with downregulated methionine metabolism. Taken together, present findings provide evidence that metabolomic changes associated with co-occurring problems may play a role in the development of severe pain. Co-occurring problems may influence each other at the metabolomic level. Because the methionine and glutathione metabolic pathways are physiologically linked, sleep problems appear to be associated with the first metabolic pathway, whereas obesity may be associated with the second. Full article

(This article belongs to the Special Issue Molecular Links between Sensory Nerves, Inflammation, and Pain 2.0)

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11 pages, 1808 KiB

Open AccessArticle

Membrane Interactivity of Capsaicin Antagonized by Capsazepine

by Maki Mizogami and Hironori Tsuchiya

Int. J. Mol. Sci. 2022, 23(7), 3971; https://doi.org/10.3390/ijms23073971 - 2 Apr 2022

Cited by 5 | Viewed by 2548

Abstract

Although the pharmacological activity of capsaicin has been explained by its specific binding to transient receptor potential vanilloid type 1, the amphiphilic structure of capsaicin may enable it to act on lipid bilayers. From a mechanistic point of view, we investigated whether capsaicin [...] Read more.

Although the pharmacological activity of capsaicin has been explained by its specific binding to transient receptor potential vanilloid type 1, the amphiphilic structure of capsaicin may enable it to act on lipid bilayers. From a mechanistic point of view, we investigated whether capsaicin and its antagonist capsazepine interact with biomimetic membranes, and how capsazepine influences the membrane effect of capsaicin. Liposomal phospholipid membranes and neuro-mimetic membranes were prepared with 1,2-dipalmitoylphosphatidylcholine and with 1-palmitoyl-2-oleoylphosphatidylcholine and sphingomyelin plus cholesterol, respectively. These membrane preparations were subjected to reactions with capsaicin and capsazepine at 0.5–250 μM, followed by measuring fluorescence polarization to determine the membrane interactivity to modify the fluidity of membranes. Both compounds acted on 1,2-dipalmitoylphosphatidylcholine bilayers and changed membrane fluidity. Capsaicin concentration-dependently interacted with neuro-mimetic membranes to increase their fluidity at low micromolar concentrations, whereas capsazepine inversely decreased the membrane fluidity. When used in combination, capsazepine inhibited the effect of capsaicin on neuro-mimetic membranes. In addition to the direct action on transmembrane ion channels, capsaicin and capsazepine share membrane interactivity, but capsazepine is likely to competitively antagonize capsaicin’s interaction with neuro-mimetic membranes at pharmacokinetically-relevant concentrations. The structure-specific membrane interactivity may be partly responsible for the analgesic effect of capsaicin. Full article

(This article belongs to the Special Issue Molecular Links between Sensory Nerves, Inflammation, and Pain 2.0)

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16 pages, 2917 KiB

Open AccessArticle

PACAP-38 Induces Transcriptomic Changes in Rat Trigeminal Ganglion Cells Related to Neuroinflammation and Altered Mitochondrial Function Presumably via PAC1/VPAC2 Receptor-Independent Mechanism

by Krisztina Takács-Lovász, József Kun, Timea Aczél, Péter Urbán, Attila Gyenesei, Kata Bölcskei, Éva Szőke and Zsuzsanna Helyes

Int. J. Mol. Sci. 2022, 23(4), 2120; https://doi.org/10.3390/ijms23042120 - 14 Feb 2022

Cited by 7 | Viewed by 3122

Abstract

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a broadly expressed neuropeptide which has diverse effects in both the peripheral and central nervous systems. While its neuroprotective effects have been shown in a variety of disease models, both animal and human data support the role [...] Read more.

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a broadly expressed neuropeptide which has diverse effects in both the peripheral and central nervous systems. While its neuroprotective effects have been shown in a variety of disease models, both animal and human data support the role of PACAP in migraine generation. Both PACAP and its truncated derivative PACAP(6-38) increased calcium influx in rat trigeminal ganglia (TG) primary sensory neurons in most experimental settings. PACAP(6-38), however, has been described as an antagonist for PACAP type I (known as PAC1), and Vasoactive Intestinal Polypeptide Receptor 2 (also known as VPAC2) receptors. Here, we aimed to compare the signaling pathways induced by the two peptides using transcriptomic analysis. Rat trigeminal ganglion cell cultures were incubated with 1 µM PACAP-38 or PACAP(6-38). Six hours later RNA was isolated, next-generation RNA sequencing was performed and transcriptomic changes were analyzed to identify differentially expressed genes. Functional analysis was performed for gene annotation using the Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Reactome databases. We found 200 common differentially expressed (DE) genes for these two neuropeptides. Both PACAP-38 and PACAP(6-38) treatments caused significant downregulation of NADH: ubiquinone oxidoreductase subunit B6 and upregulation of transient receptor potential cation channel, subfamily M, member 8. The common signaling pathways induced by both peptides indicate that they act on the same target, suggesting that PACAP activates trigeminal primary sensory neurons via a mechanism independent of the identified and cloned PAC1/VPAC2 receptor, either via another target structure or a different splice variant of PAC1/VPAC2 receptors. Identification of the target could help to understand key mechanisms of migraine. Full article

(This article belongs to the Special Issue Molecular Links between Sensory Nerves, Inflammation, and Pain 2.0)

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Review

Jump to: Editorial, Research

32 pages, 466 KiB

Open AccessReview

The Epigenetics of Neuropathic Pain: A Systematic Update

by Gábor Pethő, Boglárka Kántás, Ádám Horváth and Erika Pintér

Int. J. Mol. Sci. 2023, 24(24), 17143; https://doi.org/10.3390/ijms242417143 - 5 Dec 2023

Cited by 1 | Viewed by 2048

Abstract

Epigenetics deals with alterations to the gene expression that occur without change in the nucleotide sequence in the DNA. Various covalent modifications of the DNA and/or the surrounding histone proteins have been revealed, including DNA methylation, histone acetylation, and methylation, which can either [...] Read more.

Epigenetics deals with alterations to the gene expression that occur without change in the nucleotide sequence in the DNA. Various covalent modifications of the DNA and/or the surrounding histone proteins have been revealed, including DNA methylation, histone acetylation, and methylation, which can either stimulate or inhibit protein expression at the transcriptional level. In the past decade, an exponentially increasing amount of data has been published on the association between epigenetic changes and the pathomechanism of pain, including its most challenging form, neuropathic pain. Epigenetic regulation of the chromatin by writer, reader, and eraser proteins has been revealed for diverse protein targets involved in the pathomechanism of neuropathic pain. They include receptors, ion channels, transporters, enzymes, cytokines, chemokines, growth factors, inflammasome proteins, etc. Most work has been invested in clarifying the epigenetic downregulation of mu opioid receptors and various K⁺ channels, two types of structures mediating neuronal inhibition. Conversely, epigenetic upregulation has been revealed for glutamate receptors, growth factors, and lymphokines involved in neuronal excitation. All these data cannot only help better understand the development of neuropathic pain but outline epigenetic writers, readers, and erasers whose pharmacological inhibition may represent a novel option in the treatment of pain. Full article

(This article belongs to the Special Issue Molecular Links between Sensory Nerves, Inflammation, and Pain 2.0)

23 pages, 1991 KiB

Open AccessReview

Broaden Horizons: The Advancement of Interstitial Cystitis/Bladder Pain Syndrome

by Jin Li, Xianyanling Yi and Jianzhong Ai

Int. J. Mol. Sci. 2022, 23(23), 14594; https://doi.org/10.3390/ijms232314594 - 23 Nov 2022

Cited by 9 | Viewed by 9817

Abstract

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a debilitating disease that induces mental stress, lower urinary symptoms, and pelvic pain, therefore resulting in a decline in quality of life. The present diagnoses and treatments still lead to unsatisfactory outcomes, and novel diagnostic and therapeutic [...] Read more.

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a debilitating disease that induces mental stress, lower urinary symptoms, and pelvic pain, therefore resulting in a decline in quality of life. The present diagnoses and treatments still lead to unsatisfactory outcomes, and novel diagnostic and therapeutic modalities are needed. Although our understanding of the etiology and pathophysiology of IC/BPS is growing, the altered permeability of the impaired urothelium, the sensitized nerves on the bladder wall, and the chronic or intermittent sensory pain with inaccurate location, as well as pathologic angiogenesis, fibrosis, and Hunner lesions, all act as barriers to better diagnoses and treatments. This study aimed to summarize the comprehensive information on IC/BPS research, thereby promoting the progress of IC/BPS in the aspects of diagnosis, treatment, and prognosis. According to diverse international guidelines, the etiology of IC/BPS is associated with multiple factors, while the presence of Hunner lesions could largely distinguish the pathology, diagnosis, and treatment of non-Hunner lesions in IC/BPS patients. On the basis of the diagnosis of exclusion, the diverse present diagnostic and therapeutic procedures are undergoing a transition from a single approach to multimodal strategies targeting different potential phenotypes recommended by different guidelines. Investigations into the mechanisms involved in urinary symptoms, pain sensation, and bladder fibrosis indicate the pathophysiology of IC/BPS for further potential strategies, both in diagnosis and treatment. An overview of IC/BPS in terms of epidemiology, etiology, pathology, diagnosis, treatment, and fundamental research is provided with the latest evidence. On the basis of shared decision-making, a multimodal strategy of diagnosis and treatment targeting potential phenotypes for individual patients with IC/BPS would be of great benefit for the entire process of management. The complexity and emerging evidence on IC/BPS elicit more relevant studies and research and could optimize the management of IC/BPS patients. Full article

(This article belongs to the Special Issue Molecular Links between Sensory Nerves, Inflammation, and Pain 2.0)

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20 pages, 1475 KiB

Open AccessReview

Lysophosphatidylcholine: Potential Target for the Treatment of Chronic Pain

by Jinxuan Ren, Jiaqi Lin, Lina Yu and Min Yan

Int. J. Mol. Sci. 2022, 23(15), 8274; https://doi.org/10.3390/ijms23158274 - 27 Jul 2022

Cited by 18 | Viewed by 5845

Abstract

The bioactive lipid lysophosphatidylcholine (LPC), a major phospholipid component of oxidized low-density lipoprotein (Ox-LDL), originates from the cleavage of phosphatidylcholine by phospholipase A2 (PLA2) and is catabolized to other substances by different enzymatic pathways. LPC exerts pleiotropic effects mediated by its receptors, G [...] Read more.

The bioactive lipid lysophosphatidylcholine (LPC), a major phospholipid component of oxidized low-density lipoprotein (Ox-LDL), originates from the cleavage of phosphatidylcholine by phospholipase A2 (PLA2) and is catabolized to other substances by different enzymatic pathways. LPC exerts pleiotropic effects mediated by its receptors, G protein-coupled signaling receptors, Toll-like receptors, and ion channels to activate several second messengers. Lysophosphatidylcholine (LPC) is increasingly considered a key marker/factor positively in pathological states, especially inflammation and atherosclerosis development. Current studies have indicated that the injury of nervous tissues promotes oxidative stress and lipid peroxidation, as well as excessive accumulation of LPC, enhancing the membrane hyperexcitability to induce chronic pain, which may be recognized as one of the hallmarks of chronic pain. However, findings from lipidomic studies of LPC have been lacking in the context of chronic pain. In this review, we focus in some detail on LPC sources, biochemical pathways, and the signal-transduction system. Moreover, we outline the detection methods of LPC for accurate analysis of each individual LPC species and reveal the pathophysiological implication of LPC in chronic pain, which makes it an interesting target for biomarkers and the development of medicine regarding chronic pain. Full article

(This article belongs to the Special Issue Molecular Links between Sensory Nerves, Inflammation, and Pain 2.0)

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22 pages, 741 KiB

Open AccessReview

Neuroprotective Potential of Dendritic Cells and Sirtuins in Multiple Sclerosis

by Francesco Piacente, Marta Bottero, Andrea Benzi, Tiziana Vigo, Antonio Uccelli, Santina Bruzzone and Giovanni Ferrara

Int. J. Mol. Sci. 2022, 23(8), 4352; https://doi.org/10.3390/ijms23084352 - 14 Apr 2022

Cited by 14 | Viewed by 3663

Abstract

Myeloid cells, including parenchymal microglia, perivascular and meningeal macrophages, and dendritic cells (DCs), are present in the central nervous system (CNS) and establish an intricate relationship with other cells, playing a crucial role both in health and in neurological diseases. In this context, [...] Read more.

Myeloid cells, including parenchymal microglia, perivascular and meningeal macrophages, and dendritic cells (DCs), are present in the central nervous system (CNS) and establish an intricate relationship with other cells, playing a crucial role both in health and in neurological diseases. In this context, DCs are critical to orchestrating the immune response linking the innate and adaptive immune systems. Under steady-state conditions, DCs patrol the CNS, sampling their local environment and acting as sentinels. During neuroinflammation, the resulting activation of DCs is a critical step that drives the inflammatory response or the resolution of inflammation with the participation of different cell types of the immune system (macrophages, mast cells, T and B lymphocytes), resident cells of the CNS and soluble factors. Although the importance of DCs is clearly recognized, their exact function in CNS disease is still debated. In this review, we will discuss modern concepts of DC biology in steady-state and during autoimmune neuroinflammation. Here, we will also address some key aspects involving DCs in CNS patrolling, highlighting the neuroprotective nature of DCs and emphasizing their therapeutic potential for the treatment of neurological conditions. Recently, inhibition of the NAD⁺-dependent deac(et)ylase sirtuin 6 was demonstrated to delay the onset of experimental autoimmune encephalomyelitis, by dampening DC trafficking towards inflamed LNs. Thus, a special focus will be dedicated to sirtuins’ role in DCs functions. Full article

(This article belongs to the Special Issue Molecular Links between Sensory Nerves, Inflammation, and Pain 2.0)

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15 pages, 2317 KiB

Open AccessReview

The BDNF/TrkB Neurotrophin System in the Sensory Organs of Zebrafish

by Marialuisa Aragona, Caterina Porcino, Maria Cristina Guerrera, Giuseppe Montalbano, Rosaria Laurà, Marzio Cometa, Maria Levanti, Francesco Abbate, Teresa Cobo, Gabriel Capitelli, José A. Vega and Antonino Germanà

Int. J. Mol. Sci. 2022, 23(5), 2621; https://doi.org/10.3390/ijms23052621 - 27 Feb 2022

Cited by 24 | Viewed by 3682

Abstract

The brain-derived neurotrophic factor (BDNF) was discovered in the last century, and identified as a member of the neurotrophin family. BDNF shares approximately 50% of its amino acid with other neurotrophins such as NGF, NT-3 and NT-4/5, and its linear amino acid sequences [...] Read more.

The brain-derived neurotrophic factor (BDNF) was discovered in the last century, and identified as a member of the neurotrophin family. BDNF shares approximately 50% of its amino acid with other neurotrophins such as NGF, NT-3 and NT-4/5, and its linear amino acid sequences in zebrafish (Danio rerio) and human are 91% identical. BDNF functions can be mediated by two categories of receptors: p75NTR and Trk. Intriguingly, BDNF receptors were highly conserved in the process of evolution, as were the other NTs’ receptors. In this review, we update current knowledge about the distribution and functions of the BDNF-TrkB system in the sensory organs of zebrafish. In fish, particularly in zebrafish, the distribution and functions of BDNF and TrkB in the brain have been widely studied. Both components of the system, associated or segregated, are also present outside the central nervous system, especially in sensory organs including the inner ear, lateral line system, retina, taste buds and olfactory epithelium. Full article

(This article belongs to the Special Issue Molecular Links between Sensory Nerves, Inflammation, and Pain 2.0)

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Janus Kinase Inhibitors Improve Disease Activity and Patient-Reported Outcomes in Rheumatoid Arthritis: A Systematic Review and Meta-Analysis of 24,135 Patients

by Lilla Tóth, Márk F. Juhász, László Szabó, Alan Abada, Fruzsina Kiss, Péter Hegyi, Nelli Farkas, György Nagy and Zsuzsanna Helyes

Int. J. Mol. Sci. 2022, 23(3), 1246; https://doi.org/10.3390/ijms23031246 - 23 Jan 2022

Cited by 26 | Viewed by 6160

Abstract

Pain, fatigue, and physical activity are major determinants of life quality in rheumatoid arthritis (RA). Janus kinase (JAK) inhibitors have emerged as effective medications in RA and have been reported to exert direct analgesic effect in addition to reducing joint inflammation. This analysis [...] Read more.

Pain, fatigue, and physical activity are major determinants of life quality in rheumatoid arthritis (RA). Janus kinase (JAK) inhibitors have emerged as effective medications in RA and have been reported to exert direct analgesic effect in addition to reducing joint inflammation. This analysis aims to give an extensive summary of JAK inhibitors especially focusing on pain and patient reported outcomes (PRO). MEDLINE, CENTRAL, Embase, Scopus, and Web of Science databases were searched on the 26 October 2020, and 50 randomized controlled trials including 24,135 adult patients with active RA met the inclusion criteria. JAK inhibitors yielded significantly better results in all 36 outcomes compared to placebo. JAK monotherapy proved to be more effective than methotrexate in 9 out of 11 efficacy outcomes. In comparison to biological disease-modifying antirheumatic drugs, JAK inhibitors show statistical superiority in 13 of the 19 efficacy outcomes. Analgesic effect determined using the visual analogue scale and American College of Rheumatology (ACR) 20/50/70 response rates was significantly greater in the JAK group in all comparisons, and no significant difference regarding safety could be explored. This meta-analysis gives a comprehensive overview of JAK inhibitors and provides evidence for their superiority in improving PROs and disease activity indices in RA. Full article

(This article belongs to the Special Issue Molecular Links between Sensory Nerves, Inflammation, and Pain 2.0)

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