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18 pages, 5015 KiB

Open AccessArticle

NLRP2 Is Overexpressed in Spinal Astrocytes at the Peak of Mechanical Pain Sensitivity during Complete Freund Adjuvant-Induced Persistent Pain

by László Ducza, Péter Szücs, Krisztina Hegedűs, Erzsébet Bakk, Andrea Gajtkó, Ildikó Wéber and Krisztina Holló

Int. J. Mol. Sci. 2021, 22(21), 11408; https://doi.org/10.3390/ijms222111408 - 22 Oct 2021

Cited by 18 | Viewed by 2512

Abstract

Our earlier findings revealed that interleukin-1 receptor type-1 (IL-1R1) was overexpressed in spinal neurons, and IL-1R1-deficient mice showed significant attenuation of thermal and mechanical allodynia during the course of the Complete Freund adjuvant (CFA)-induced persistent pain model. In the present study, we found [...] Read more.

Our earlier findings revealed that interleukin-1 receptor type-1 (IL-1R1) was overexpressed in spinal neurons, and IL-1R1-deficient mice showed significant attenuation of thermal and mechanical allodynia during the course of the Complete Freund adjuvant (CFA)-induced persistent pain model. In the present study, we found that a ligand of IL-1R1, termed interleukin-1β (IL-1β), is also significantly overexpressed at the peak of mechanical pain sensitivity in the CFA-evoked pain model. Analysis of cellular distribution and modeling using IMARIS software showed that in the lumbar spinal dorsal horn, IL-1β is significantly elevated by astrocytic expression. Maturation of IL-1β to its active form is facilitated by the formation of the multiprotein complex called inflammasome; thus, we tested the expression of NOD-like receptor proteins (NLRPs) in astrocytes. At the peak of mechanical allodynia, we found expression of the NLRP2 inflammasome sensor and its significantly elevated co-localization with the GFAP astrocytic marker, while NLRP3 was moderately present and NLRP1 showed total segregation from the astrocytic profiles. Our results indicate that peripheral CFA injection induces NLRP2 inflammasome and IL-1β expression in spinal astrocytes. The release of mature IL-1β can contribute to the maintenance of persistent pain by acting on its neuronally expressed receptor, which can lead to altered neuronal excitability. Full article

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

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18 pages, 4413 KiB

Open AccessArticle

Protective Effects of PACAP in a Rat Model of Diabetic Neuropathy

by Peter Kiss, Eszter Banki, Balazs Gaszner, Daniel Nagy, Zsuzsanna Helyes, Endre Pal, Gyongyver Reman, Gabor Toth, Andrea Tamas and Dora Reglodi

Int. J. Mol. Sci. 2021, 22(19), 10691; https://doi.org/10.3390/ijms221910691 - 2 Oct 2021

Cited by 5 | Viewed by 2995

Abstract

Pituitary adenylate cyclase-activating peptide (PACAP) is a neuropeptide with a widespread occurrence and diverse effects. PACAP has well-documented neuro- and cytoprotective effects, proven in numerous studies. Among others, PACAP is protective in models of diabetes-associated diseases, such as diabetic nephropathy and retinopathy. As [...] Read more.

Pituitary adenylate cyclase-activating peptide (PACAP) is a neuropeptide with a widespread occurrence and diverse effects. PACAP has well-documented neuro- and cytoprotective effects, proven in numerous studies. Among others, PACAP is protective in models of diabetes-associated diseases, such as diabetic nephropathy and retinopathy. As the neuropeptide has strong neurotrophic and neuroprotective actions, we aimed at investigating the effects of PACAP in a rat model of streptozotocin-induced diabetic neuropathy, another common complication of diabetes. Rats were treated with PACAP1-38 every second day for 8 weeks starting simultaneously with the streptozotocin injection. Nerve fiber morphology was examined with electron microscopy, chronic neuronal activation in pain processing centers was studied with FosB immunohistochemistry, and functionality was assessed by determining the mechanical nociceptive threshold. PACAP treatment did not alter body weight or blood glucose levels during the 8-week observation period. However, PACAP attenuated the mechanical hyperalgesia, compared to vehicle-treated diabetic animals, and it markedly reduced the morphological signs characteristic for neuropathy: axon–myelin separation, mitochondrial fission, unmyelinated fiber atrophy, and basement membrane thickening of endoneurial vessels. Furthermore, PACAP attenuated the increase in FosB immunoreactivity in the dorsal spinal horn and periaqueductal grey matter. Our results show that PACAP is a promising therapeutic agent in diabetes-associated complications, including diabetic neuropathy. Full article

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

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19 pages, 5745 KiB

Open AccessArticle

Adipose-Derived Stem Cells and Their Derived Microvesicles Ameliorate Detrusor Overactivity Secondary to Bilateral Partial Iliac Arterial Occlusion-Induced Bladder Ischemia

by Bing-Juin Chiang, Chun-Hou Liao, Su-Han Mao and Chiang-Ting Chien

Int. J. Mol. Sci. 2021, 22(13), 7000; https://doi.org/10.3390/ijms22137000 - 29 Jun 2021

Cited by 5 | Viewed by 2526

Abstract

(1) Background: We established a new bladder ischemia rat model through bilateral partial iliac arterial occlusion (BPAO) and investigated the therapeutic effect of adipose-derived stem cells (ADSCs) and ADSC-derived microvesicles (MVs); (2) Methods: The study included four groups: (1) sham, (2) BPAO, (3) [...] Read more.

(1) Background: We established a new bladder ischemia rat model through bilateral partial iliac arterial occlusion (BPAO) and investigated the therapeutic effect of adipose-derived stem cells (ADSCs) and ADSC-derived microvesicles (MVs); (2) Methods: The study included four groups: (1) sham, (2) BPAO, (3) BPAO + ADSCs, and (4) BPAO + ADSC-derived MVs. Female Wistar rats with BPAO were injected with ADSCs or ADSC-derived MVs through the femoral artery. Doppler flowmetry and real-time laser speckle contrast imaging were performed to quantify blood flow in the common iliac arteries and bladder microcirculation. A 24-h behavior study and transcystometrogram were conducted after 2 weeks. Bladder histology, immunostaining, and lipid peroxidation assay were performed. The expressions of P2X2, P2X3, M2, and M3 receptors and nerve growth factor (NGF) were evaluated; (3) Results: BPAO significantly reduced bladder microcirculation, intercontraction interval (ICI), and bladder volume and increased the amplitude of nonvoiding contraction, neutrophil infiltration, and malondialdehyde and NGF levels. ADSCs and ADSC-derived MVs significantly ameliorated these effects. The results of Western blot showed that the BPAO group exhibited the highest expression of M3 and P2X2 receptors. ADSCs significantly attenuated the expressions of M2 and P2X2 receptors. ADSC-derived MVs significantly attenuated the expressions of M3 and P2X2 receptors; (4) Conclusions: ADSCs and ADSC-derived MVs ameliorated the adverse effects of BPAO including bladder overactivity, bladder ischemia, and oxidative stress. Inflammation, muscarinic signaling, purinergic signaling, and NGF might be involved in the therapeutic mechanism. Full article

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

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16 pages, 4287 KiB

Open AccessArticle

Regulatory Influence of Galanin and GALR1/GALR2 Receptors on Inflamed Uterus Contractility in Pigs

by Barbara Jana, Jarosław Całka and Bartosz Miciński

Int. J. Mol. Sci. 2021, 22(12), 6415; https://doi.org/10.3390/ijms22126415 - 15 Jun 2021

Cited by 6 | Viewed by 2319

Abstract

Uterine inflammation is a very common and serious pathology in domestic animals, the development and progression of which often result from disturbed myometrial contractility. We investigated the effect of inflammation on the protein expression of galanin (GAL) receptor subtypes (GALR)1 and GALR2 in [...] Read more.

Uterine inflammation is a very common and serious pathology in domestic animals, the development and progression of which often result from disturbed myometrial contractility. We investigated the effect of inflammation on the protein expression of galanin (GAL) receptor subtypes (GALR)1 and GALR2 in myometrium and their role in the contractile amplitude and frequency of an inflamed gilt uterus. The gilts of the E. coli and SAL groups received E. coli suspension or saline in their uteri, respectively, and only laparotomy was performed (CON group). Eight days later, the E. coli group developed severe acute endometritis and lowered GALR1 protein expression in the myometrium. Compared to the pretreatment period, GAL (10⁻⁷ M) reduced the amplitude and frequency in myometrium and endometrium/myometrium of the CON and SAL groups, the amplitude in both stripes and frequency in endometrium/myometrium of the E. coli group. In this group, myometrial frequency after using GAL increased, and it was higher than in other groups. GALR2 antagonist diminished the decrease in amplitude in myometrium and the frequency in endometrium/myometrium (SAL, E. coli groups) induced by GAL (10⁻⁷ M). GALR1/GALR2 antagonist and GAL (10⁻⁷ M) reversed the decrease in amplitude and diminished the decrease in frequency in both examined stripes (CON, SAL groups), and diminished the drop in amplitude and abolished the rise in the frequency in the myometrium (E. coli group). In summary, the inflammation reduced GALR1 protein expression in pig myometrium, and GALR1 and GALR2 participated in the contractile regulation of an inflamed uterus. Full article

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

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12 pages, 2427 KiB

Open AccessArticle

(-)-Englerin-A Has Analgesic and Anti-Inflammatory Effects Independent of TRPC4 and 5

by João de Sousa Valente, Khadija M Alawi, Sabah Bharde, Ali A. Zarban, Xenia Kodji, Dibesh Thapa, Fulye Argunhan, Brentton Barrett, Istvan Nagy and Susan D. Brain

Int. J. Mol. Sci. 2021, 22(12), 6380; https://doi.org/10.3390/ijms22126380 - 15 Jun 2021

Cited by 3 | Viewed by 2824

Abstract

Recently, we found that the deletion of TRPC5 leads to increased inflammation and pain-related behaviour in two animal models of arthritis. (-)-Englerin A (EA), an extract from the East African plant Phyllanthus engleri has been identified as a TRPC4/5 agonist. Here, we studied [...] Read more.

Recently, we found that the deletion of TRPC5 leads to increased inflammation and pain-related behaviour in two animal models of arthritis. (-)-Englerin A (EA), an extract from the East African plant Phyllanthus engleri has been identified as a TRPC4/5 agonist. Here, we studied whether or not EA has any anti-inflammatory and analgesic properties via TRPC4/5 in the carrageenan model of inflammation. We found that EA treatment in CD1 mice inhibited thermal hyperalgesia and mechanical allodynia in a dose-dependent manner. Furthermore, EA significantly reduced the volume of carrageenan-induced paw oedema and the mass of the treated paws. Additionally, in dorsal root ganglion (DRG) neurons cultured from WT 129S1/SvIm mice, EA induced a dose-dependent cobalt uptake that was surprisingly preserved in cultured DRG neurons from 129S1/SvIm TRPC5 KO mice. Likewise, EA-induced anti-inflammatory and analgesic effects were preserved in the carrageenan model in animals lacking TRPC5 expression or in mice treated with TRPC4/5 antagonist ML204.This study demonstrates that while EA activates a sub-population of DRG neurons, it induces a novel TRPC4/5-independent analgesic and anti-inflammatory effect in vivo. Future studies are needed to elucidate the molecular and cellular mechanisms underlying EA’s anti-inflammatory and analgesic effects. Full article

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

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15 pages, 5261 KiB

Open AccessArticle

Pharmacological Evidence on Augmented Antiallodynia Following Systemic Co-Treatment with GlyT-1 and GlyT-2 Inhibitors in Rat Neuropathic Pain Model

by Amir Mohammadzadeh, Péter P. Lakatos, Mihály Balogh, Ferenc Zádor, Dávid Árpád Karádi, Zoltán S. Zádori, Kornél Király, Anna Rita Galambos, Szilvia Barsi, Pál Riba, Sándor Benyhe, László Köles, Tamás Tábi, Éva Szökő, Laszlo G. Harsing, Jr. and Mahmoud Al-Khrasani

Int. J. Mol. Sci. 2021, 22(5), 2479; https://doi.org/10.3390/ijms22052479 - 1 Mar 2021

Cited by 14 | Viewed by 3221

Abstract

The limited effect of current medications on neuropathic pain (NP) has initiated large efforts to develop effective treatments. Animal studies showed that glycine transporter (GlyT) inhibitors are promising analgesics in NP, though concerns regarding adverse effects were raised. We aimed to study NFPS [...] Read more.

The limited effect of current medications on neuropathic pain (NP) has initiated large efforts to develop effective treatments. Animal studies showed that glycine transporter (GlyT) inhibitors are promising analgesics in NP, though concerns regarding adverse effects were raised. We aimed to study NFPS and Org-25543, GlyT-1 and GlyT-2 inhibitors, respectively and their combination in rat mononeuropathic pain evoked by partial sciatic nerve ligation. Cerebrospinal fluid (CSF) glycine content was also determined by capillary electrophoresis. Subcutaneous (s.c.) 4 mg/kg NFPS or Org-25543 showed analgesia following acute administration (30–60 min). Small doses of each compound failed to produce antiallodynia up to 180 min after the acute administration. However, NFPS (1 mg/kg) produced antiallodynia after four days of treatment. Co-treatment with subanalgesic doses of NFPS (1 mg/kg) and Org-25543 (2 mg/kg) produced analgesia at 60 min and thereafter meanwhile increased significantly the CSF glycine content. This combination alleviated NP without affecting motor function. Test compounds failed to activate G-proteins in spinal cord. To the best of our knowledge for the first time we demonstrated augmented analgesia by combining GlyT-1 and 2 inhibitors. Increased CSF glycine content supports involvement of glycinergic system. Combining selective GlyT inhibitors or developing non-selective GlyT inhibitors might have therapeutic value in NP. Full article

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

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28 pages, 3935 KiB

Open AccessArticle

Spinal Excitatory Dynorphinergic Interneurons Contribute to Burn Injury-Induced Nociception Mediated by Phosphorylated Histone 3 at Serine 10 in Rodents

by Angelika Varga, Zoltán Mészár, Miklós Sivadó, Tímea Bácskai, Bence Végh, Éva Kókai, István Nagy and Péter Szücs

Int. J. Mol. Sci. 2021, 22(5), 2297; https://doi.org/10.3390/ijms22052297 - 25 Feb 2021

Cited by 8 | Viewed by 3228

Abstract

The phosphorylation of serine 10 in histone 3 (p-S10H3) has recently been demonstrated to participate in spinal nociceptive processing. However, superficial dorsal horn (SDH) neurons involved in p-S10H3-mediated nociception have not been fully characterized. In the present work, we combined immunohistochemistry, in situ [...] Read more.

The phosphorylation of serine 10 in histone 3 (p-S10H3) has recently been demonstrated to participate in spinal nociceptive processing. However, superficial dorsal horn (SDH) neurons involved in p-S10H3-mediated nociception have not been fully characterized. In the present work, we combined immunohistochemistry, in situ hybridization with the retrograde labeling of projection neurons to reveal the subset of dorsal horn neurons presenting an elevated level of p-S10H3 in response to noxious heat (60 °C), causing burn injury. Projection neurons only represented a small percentage (5%) of p-S10H3-positive cells, while the greater part of them belonged to excitatory SDH interneurons. The combined immunolabeling of p-S10H3 with markers of already established interneuronal classes of the SDH revealed that the largest subset of neurons with burn injury-induced p-S10H3 expression was dynorphin immunopositive in mice. Furthermore, the majority of p-S10H3-expressing dynorphinergic neurons proved to be excitatory, as they lacked Pax-2 and showed Lmx1b-immunopositivity. Thus, we showed that neurochemically heterogeneous SDH neurons exhibit the upregulation of p-S10H3 shortly after noxious heat-induced burn injury and consequential tissue damage, and that a dedicated subset of excitatory dynorphinergic neurons is likely a key player in the development of central sensitization via the p-S10H3 mediated pathway. Full article

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

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13 pages, 2551 KiB

Open AccessArticle

Capsaicin-Sensitive Peptidergic Sensory Nerves Are Anti-Inflammatory Gatekeepers in the Hyperacute Phase of a Mouse Rheumatoid Arthritis Model

by Bálint Botz, Gábor Kriszta, Kata Bölcskei, Ádám István Horváth, Attila Mócsai and Zsuzsanna Helyes

Int. J. Mol. Sci. 2021, 22(4), 1682; https://doi.org/10.3390/ijms22041682 - 8 Feb 2021

Cited by 4 | Viewed by 2819

Abstract

Capsaicin-sensitive peptidergic sensory nerves play complex, mainly protective regulatory roles in the inflammatory cascade of the joints via neuropeptide mediators, but the mechanisms of the hyperacute arthritis phase has not been investigated. Therefore, we studied the involvement of these afferents in the early, [...] Read more.

Capsaicin-sensitive peptidergic sensory nerves play complex, mainly protective regulatory roles in the inflammatory cascade of the joints via neuropeptide mediators, but the mechanisms of the hyperacute arthritis phase has not been investigated. Therefore, we studied the involvement of these afferents in the early, “black box” period of a rheumatoid arthritis (RA) mouse model. Capsaicin-sensitive fibres were defunctionalized by pretreatment with the ultrapotent capsaicin analog resiniferatoxin and arthritis was induced by K/BxN arthritogenic serum. Disease severity was assessed by clinical scoring, reactive oxygen species (ROS) burst by chemiluminescent, vascular permeability by fluorescent in vivo imaging. Contrast-enhanced magnetic resonance imaging was used to correlate the functional and morphological changes. After sensory desensitization, both early phase ROS-burst and vascular leakage were significantly enhanced, which was later followed by the increased clinical severity scores. Furthermore, the early vascular leakage and ROS-burst were found to be good predictors of later arthritis severity. We conclude that the anti-inflammatory role of peptidergic afferents depends on their activity in the hyperacute phase, characterized by decreased cellular and vascular inflammatory components presumably via anti-inflammatory neuropeptide release. Therefore, these fibres might serve as important gatekeepers in RA. Full article

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

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28 pages, 3682 KiB

Open AccessArticle

Computational Functional Genomics-Based AmpliSeq™ Panel for Next-Generation Sequencing of Key Genes of Pain

by Dario Kringel, Sebastian Malkusch, Eija Kalso and Jörn Lötsch

Int. J. Mol. Sci. 2021, 22(2), 878; https://doi.org/10.3390/ijms22020878 - 16 Jan 2021

Cited by 2 | Viewed by 4478

Abstract

The genetic background of pain is becoming increasingly well understood, which opens up possibilities for predicting the individual risk of persistent pain and the use of tailored therapies adapted to the variant pattern of the patient’s pain-relevant genes. The individual variant pattern of [...] Read more.

The genetic background of pain is becoming increasingly well understood, which opens up possibilities for predicting the individual risk of persistent pain and the use of tailored therapies adapted to the variant pattern of the patient’s pain-relevant genes. The individual variant pattern of pain-relevant genes is accessible via next-generation sequencing, although the analysis of all “pain genes” would be expensive. Here, we report on the development of a cost-effective next generation sequencing-based pain-genotyping assay comprising the development of a customized AmpliSeq™ panel and bioinformatics approaches that condensate the genetic information of pain by identifying the most representative genes. The panel includes 29 key genes that have been shown to cover 70% of the biological functions exerted by a list of 540 so-called “pain genes” derived from transgenic mice experiments. These were supplemented by 43 additional genes that had been independently proposed as relevant for persistent pain. The functional genomics covered by the resulting 72 genes is particularly represented by mitogen-activated protein kinase of extracellular signal-regulated kinase and cytokine production and secretion. The present genotyping assay was established in 61 subjects of Caucasian ethnicity and investigates the functional role of the selected genes in the context of the known genetic architecture of pain without seeking functional associations for pain. The assay identified a total of 691 genetic variants, of which many have reports for a clinical relevance for pain or in another context. The assay is applicable for small to large-scale experimental setups at contemporary genotyping costs. Full article

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

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Review

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24 pages, 3601 KiB

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Kynurenine Pathway of Tryptophan Metabolism in Migraine and Functional Gastrointestinal Disorders

by Michal Fila, Jan Chojnacki, Elzbieta Pawlowska, Joanna Szczepanska, Cezary Chojnacki and Janusz Blasiak

Int. J. Mol. Sci. 2021, 22(18), 10134; https://doi.org/10.3390/ijms221810134 - 20 Sep 2021

Cited by 28 | Viewed by 6847

Abstract

Migraine, the leading cause of disability in the population aged below 50, is associated with functional gastrointestinal (GI) disorders (FGIDs) such as functional nausea, cyclic vomiting syndrome, and irritable bowel syndrome (IBS). Conversely, changes in intestinal GI transit may cause diarrhea or constipation [...] Read more.

Migraine, the leading cause of disability in the population aged below 50, is associated with functional gastrointestinal (GI) disorders (FGIDs) such as functional nausea, cyclic vomiting syndrome, and irritable bowel syndrome (IBS). Conversely, changes in intestinal GI transit may cause diarrhea or constipation and are a component of the autonomic symptoms associated with pre- and post-dorsal phases of migraine attack. These mutual relationships provoke a question on a common trigger in migraine and FGIDs. The kynurenine (l-kyn) pathway (KP) is the major route for l-tryptophan (l-Trp) metabolism and transforms l-Trp into several neuroactive compounds. Changes in KP were reported in both migraine and FGIDs. Migraine was largely untreatable, but several drugs approved lately by the FDA, including monoclonal antibodies for calcitonin gene-related peptide (CGRP) and its receptor, create a hope for a breakthrough in migraine treatment. Derivatives of l-kyn were efficient in pain relief with a mechanism including CGRP inhibition. KP products are important ligands to the aryl hydrocarbon receptor (AhR), whose activation is implicated in the pathogenesis of GI and migraine. Toll-like receptors (TLRs) may play a role in migraine and IBS pathogeneses, and KP metabolites detected downstream of TLR activation may be an IBS marker. The TLR4 signaling was observed in initiating and maintaining migraine-like behavior through myeloid differentiation primary response gene 88 (MyD88) in the mouse. The aim of this review is to justify the view that KP modulation may provide common triggers for migraine and FGIDs with the involvement of TLR, AhR, and MyD88 activation. Full article

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

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11 pages, 566 KiB

Open AccessReview

Is “Delayed Onset Muscle Soreness” a False Friend? The Potential Implication of the Fascial Connective Tissue in Post-Exercise Discomfort

by Jan Wilke and Michael Behringer

Int. J. Mol. Sci. 2021, 22(17), 9482; https://doi.org/10.3390/ijms22179482 - 31 Aug 2021

Cited by 22 | Viewed by 13640

Abstract

Strenuous and unaccustomed exercise frequently lead to what has been coined “delayed onset muscle soreness” (DOMS). As implied by this term, it has been proposed that the associated pain and stiffness stem from micro-lesions, inflammation, or metabolite accumulation within the skeletal muscle. However, [...] Read more.

Strenuous and unaccustomed exercise frequently lead to what has been coined “delayed onset muscle soreness” (DOMS). As implied by this term, it has been proposed that the associated pain and stiffness stem from micro-lesions, inflammation, or metabolite accumulation within the skeletal muscle. However, recent research points towards a strong involvement of the connective tissue. First, according to anatomical studies, the deep fascia displays an intimate structural relationship with the underlying skeletal muscle and may therefore be damaged during excessive loading. Second, histological and experimental studies suggest a rich supply of algogenic nociceptors whose stimulation evokes stronger pain responses than muscle irritation. Taken together, the findings support the hypothesis that DOMS originates in the muscle-associated connective tissue rather than in the muscle itself. Sports and fitness professionals designing exercise programs should hence consider fascia-oriented methods and techniques (e.g., foam rolling, collagen supplementation) when aiming to treat or prevent DOMS. Full article

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

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16 pages, 1146 KiB

Open AccessReview

Protease Activated Receptors and Arthritis

by Flora Lucena and Jason J. McDougall

Int. J. Mol. Sci. 2021, 22(17), 9352; https://doi.org/10.3390/ijms22179352 - 28 Aug 2021

Cited by 11 | Viewed by 3729

Abstract

The catabolic and destructive activity of serine proteases in arthritic joints is well known; however, these enzymes can also signal pain and inflammation in joints. For example, thrombin, trypsin, tryptase, and neutrophil elastase cleave the extracellular N-terminus of a family of G protein-coupled [...] Read more.

The catabolic and destructive activity of serine proteases in arthritic joints is well known; however, these enzymes can also signal pain and inflammation in joints. For example, thrombin, trypsin, tryptase, and neutrophil elastase cleave the extracellular N-terminus of a family of G protein-coupled receptors and the remaining tethered ligand sequence then binds to the same receptor to initiate a series of molecular signalling processes. These protease activated receptors (PARs) pervade multiple tissues and cells throughout joints where they have the potential to regulate joint homeostasis. Overall, joint PARs contribute to pain, inflammation, and structural integrity by altering vascular reactivity, nociceptor sensitivity, and tissue remodelling. This review highlights the therapeutic potential of targeting PARs to alleviate the pain and destructive nature of elevated proteases in various arthritic conditions. Full article

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

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