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The Signaling and Cellular Mechanisms of Pain

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Signaling".

Deadline for manuscript submissions: closed (10 November 2023) | Viewed by 18718

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Dr. Alessandra Pacini

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Department of Experimental and Clinical Medicine (DMSC), Anatomy Section, School of Human Health Sciences, University of Florence, Florence, Italy
Interests: neuropathic pain; blood–brain barrier; cadmium toxicity; neuroprotection
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Dear Colleagues,

The physiological perception of pain is essential for the brain to engage appropriate responses against noxious stimuli. In pathological conditions, such as chronicity, pain lacks the positive characteristic of alarm evolving to disease. Based on three major characteristics, namely symptoms, mechanisms and syndromes, pain may be classified into three classes: nociceptive, neuropathic, and inflammatory pain. The events that follow one another leading to the onset of pain can originate from various sources and consist of three events: the transduction, transmission and modulation of noxious stimuli.

The cell type most involved in the various phases of the pain projection are the sensory neurons whose sensitivity can be modulated by various mediators. The latter trigger the activation of many different signaling cascades, which, in turn, determine the response to painful stimuli.

Although many studies have shed light on some components of the intracellular signal transduction cascades, the signaling pathways downstream of receptor–ligand interactions are still largely unknown.

Another very important aspect to consider is the plethora of plastic changes that take place in the peripheral and the central nervous systems to contribute to pain perception. In addition, the molecular mechanism responsible for neuronal and glial plasticity is widely accepted as the mechanism underpinning the transition from acute/physiological pain to chronic/pathological pain.

Thus, understanding the molecular and cellular mechanisms of pain is essential for the advance of pain physiopathology knowledge, for the identification of new therapeutic targets and, finally, to improve its management.

Prof. Dr. Alessandra Pacini
Guest Editor

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Keywords

nociception
neuropathic pain
visceral pain
pain pathophysiological pathways
glia
analgesia

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Related Special Issue

The Signaling and Cellular Mechanisms of Pain—Second Edition in Cells (1 article)

Published Papers (8 papers)

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Research

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16 pages, 3099 KiB

Open AccessArticle

Super-Resolution Analysis of the Origins of the Elementary Events of ER Calcium Release in Dorsal Root Ganglion Neurons

by Miriam E. Hurley, Shihab S. Shah, Thomas M. D. Sheard, Hannah M. Kirton, Derek S. Steele, Nikita Gamper and Izzy Jayasinghe

Cells 2024, 13(1), 38; https://doi.org/10.3390/cells13010038 - 23 Dec 2023

Viewed by 2056

Abstract

Coordinated events of calcium (Ca²⁺) released from the endoplasmic reticulum (ER) are key second messengers in excitable cells. In pain-sensing dorsal root ganglion (DRG) neurons, these events can be observed as Ca²⁺ sparks, produced by a combination of ryanodine receptors (RyR) and inositol 1,4,5-triphosphate receptors (IP3R1). These microscopic signals offer the neuronal cells with a possible means of modulating the subplasmalemmal Ca²⁺ handling, initiating vesicular exocytosis. With super-resolution dSTORM and expansion microscopies, we visualised the nanoscale distributions of both RyR and IP3R1 that featured loosely organised clusters in the subplasmalemmal regions of cultured rat DRG somata. We adapted a novel correlative microscopy protocol to examine the nanoscale patterns of RyR and IP3R1 in the locality of each Ca²⁺ spark. We found that most subplasmalemmal sparks correlated with relatively small groups of RyR whilst larger sparks were often associated with larger groups of IP3R1. These data also showed spontaneous Ca²⁺ sparks in <30% of the subplasmalemmal cell area but consisted of both these channel species at a 3.8–5 times higher density than in nonactive regions of the cell. Taken together, these observations reveal distinct patterns and length scales of RyR and IP3R1 co-clustering at contact sites between the ER and the surface plasmalemma that encode the positions and the quantity of Ca²⁺ released at each Ca²⁺ spark. Full article

(This article belongs to the Special Issue The Signaling and Cellular Mechanisms of Pain)

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19 pages, 4277 KiB

Open AccessArticle

Innate Immunity and Sex: Distinct Inflammatory Profiles Associated with Murine Pain in Acute Synovitis

by Natália Valdrighi, Arjen B. Blom, Juliana P. Vago, Henk M. van Beuningen, Elly L. Vitters, Monique M. Helsen, Birgitte Walgreen, Onno J. Arntz, Marije I. Koenders, Peter M. van der Kraan, Esmeralda N. Blaney Davidson and Fons A. J. van de Loo

Cells 2023, 12(14), 1913; https://doi.org/10.3390/cells12141913 - 22 Jul 2023

Viewed by 1572

Abstract

Joint pain severity in arthritic diseases differs between sexes and is often more pronounced in women. This disparity is thought to stem from biological mechanisms, particularly innate immunity, yet the understanding of sex-specific differences in arthritic pain remains incomplete. This study aims to investigate these disparities using an innate immunity-driven inflammation model induced by intra-articular injections of Streptococcus Cell Wall fragments to mimic both acute and pre-sensitized joint conditions. Nociceptive behavior was evaluated via gait analysis and static weight-bearing, and inflammation was evaluated via joint histology and the synovial gene expression involved in immune response. Although acute inflammation and pain severity were comparable between sexes, distinct associations between synovial inflammatory gene expression and static nociceptive behavior emerged. These associations delineated sex-specific relationships with pain, highlighting differential gene interactions (Il6 versus Cybb on day 1 and Cyba/Gas6 versus Nos2 on day 8) between sexes. In conclusion, our study found that, despite similar pain severity between sexes, the association of inflammatory synovial genes revealed sex-specific differences in the molecular inflammatory mechanisms underlying pain. These findings suggest a path towards more personalized treatment strategies for pain management in arthritis and other inflammatory joint diseases. Full article

(This article belongs to the Special Issue The Signaling and Cellular Mechanisms of Pain)

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15 pages, 3897 KiB

Open AccessArticle

Translation of Experimental Findings from Animal to Human Biology: Identification of Neuronal Mineralocorticoid and Glucocorticoid Receptors in a Sectioned Main Nerve Trunk of the Leg

by Sascha Tafelski, Jan D. Wandrey, Mohammed Shaqura, Xueqi Hong, Antje Beyer, Michael Schäfer and Shaaban A. Mousa

Cells 2023, 12(13), 1785; https://doi.org/10.3390/cells12131785 - 5 Jul 2023

Cited by 1 | Viewed by 1406

Abstract

The activation of the mineralocorticoid (MR) and glucocorticoid (GR) receptors on peripheral sensory neurons seems to modify pain perception through both direct non-genomic and indirect genomic pathways. These distinct subpopulations of sensory neurons are not known for peripheral human nerves. Therefore, we examined MR and GR on subpopulations of sensory neurons in sectioned human and rat peripheral nerves. Real-time PCR (RT-PCR) and double immunofluorescence confocal analysis of MR and GR with the neuronal markers PGP9.5, neurofilament 200 (NF200), and the potential pain signaling molecules CGRP, Nav1.8, and TRPV1 were performed in human and rat nerve tissue. We evaluated mechanical hyperalgesia after intrathecal administration of GR and MR agonists. We isolated MR- and GR-specific mRNA from human peripheral nerves using RT-PCR. Our double immunofluorescence analysis showed that the majority of GR colocalized with NF200 positive, myelinated, mechanoreceptive A-fibers and, to a lesser extent, with peripheral peptidergic CGRP-immunoreactive sensory nerve fibers in humans and rats. However, the majority of MR colocalized with CGRP in rat as well as human nerve tissue. Importantly, there was an abundant colocalization of MR with the pain signaling molecules TRPV1, CGRP, and Nav1.8 in human as well as rat nerve tissue. The intrathecal application of the GR agonist reduced, and intrathecal administration of an MR agonist increased, mechanical hyperalgesia in rats. Altogether, these findings support a translational approach in mammals that aims to explain the modulation of sensory information through MR and GR activation. Our findings show a significant overlap between humans and rats in MR and GR expression in peripheral sensory neurons. Full article

(This article belongs to the Special Issue The Signaling and Cellular Mechanisms of Pain)

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16 pages, 3338 KiB

Open AccessArticle

Neuropathic-like Nociception and Spinal Cord Neuroinflammation Are Dependent on the TRPA1 Channel in Multiple Sclerosis Models in Mice

by Diéssica Padilha Dalenogare, Daniel Souza Monteiro de Araújo, Lorenzo Landini, Mustafa Titiz, Gaetano De Siena, Francesco De Logu, Pierangelo Geppetti, Romina Nassini and Gabriela Trevisan

Cells 2023, 12(11), 1511; https://doi.org/10.3390/cells12111511 - 30 May 2023

Cited by 2 | Viewed by 2052

Abstract

Background: Transient receptor potential ankyrin 1 (TRPA1) activation is implicated in neuropathic pain-like symptoms. However, whether TRPA1 is solely implicated in pain-signaling or contributes to neuroinflammation in multiple sclerosis (MS) is unknown. Here, we evaluated the TRPA1 role in neuroinflammation underlying pain-like symptoms using two different models of MS. Methods: Using a myelin antigen, Trpa1⁺^/+ or Trpa1⁻^/− female mice developed relapsing-remitting experimental autoimmune encephalomyelitis (RR-EAE) (Quil A as adjuvant) or progressive experimental autoimmune encephalomyelitis (PMS)-EAE (complete Freund’s adjuvant). The locomotor performance, clinical scores, mechanical/cold allodynia, and neuroinflammatory MS markers were evaluated. Results: Mechanical and cold allodynia detected in RR-EAE, or PMS-EAE Trpa1⁺^/+ mice, were not observed in Trpa1⁻^/− mice. The increased number of cells labeled for ionized calcium-binding adapter molecule 1 (Iba1) or glial fibrillary acidic protein (GFAP), two neuroinflammatory markers in the spinal cord observed in both RR-EAE or PMS-EAE Trpa1⁺^/+ mice, was reduced in Trpa1⁻^/− mice. By Olig2 marker and luxol fast blue staining, prevention of the demyelinating process in Trpa1⁻^/− induced mice was also detected. Conclusions: Present results indicate that the proalgesic role of TRPA1 in EAE mouse models is primarily mediated by its ability to promote spinal neuroinflammation and further strengthen the channel inhibition to treat neuropathic pain in MS. Full article

(This article belongs to the Special Issue The Signaling and Cellular Mechanisms of Pain)

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20 pages, 4613 KiB

Open AccessArticle

Targeting Neuroinflammation with Abscisic Acid Reduces Pain Sensitivity in Females and Hyperactivity in Males of an ADHD Mice Model

by María Meseguer-Beltrán, Sandra Sánchez-Sarasúa, Marc Landry, Nora Kerekes and Ana María Sánchez-Pérez

Cells 2023, 12(3), 465; https://doi.org/10.3390/cells12030465 - 31 Jan 2023

Cited by 5 | Viewed by 3172

Abstract

Attention deficit/hyperactivity disorder (ADHD) is a neurodevelopmental syndrome characterized by dopaminergic dysfunction. In this study, we aimed to demonstrate that there is a link between dopaminergic deficit and neuroinflammation that underlies ADHD symptoms. We used a validated ADHD mice model involving perinatal 6-OHDA lesions. The animals received abscisic acid (ABA), an anti-inflammatory phytohormone, at a concentration of 20 mg/L (drinking water) for one month. We tested a battery of behavior tests, learning and memory, anxiety, social interactions, and pain thresholds in female and male mice (control and lesioned, with or without ABA treatment). Postmortem, we analyzed microglia morphology and Ape1 expression in specific brain areas related to the descending pain inhibitory pathway. In females, the dopaminergic deficit increased pain sensitivity but not hyperactivity. In contrast, males displayed hyperactivity but showed no increased pain sensitivity. In females, pain sensitivity was associated with inflammatory microglia and lower Ape1 levels in the anterior cingulate cortex (ACC) and posterior insula cortex (IC). In addition, ABA treatment alleviated pain sensitivity concomitant with reduced inflammation and normalized APE1. In males, ABA reduced hyperactivity but had no significant effect on inflammation in these areas. This is the first study proving a sex-dependent association between dopamine dysfunction and inflammation in specific brain areas, hence leading to different behavioral outcomes in a mouse model of ADHD. These findings provide new clues for potential treatments for ADHD. Full article

(This article belongs to the Special Issue The Signaling and Cellular Mechanisms of Pain)

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28 pages, 4054 KiB

Open AccessArticle

Pharmacological Evidence of the Important Roles of CCR1 and CCR3 and Their Endogenous Ligands CCL2/7/8 in Hypersensitivity Based on a Murine Model of Neuropathic Pain

by Katarzyna Pawlik, Katarzyna Ciapała, Agata Ciechanowska, Klaudia Kwiatkowski and Joanna Mika

Cells 2023, 12(1), 98; https://doi.org/10.3390/cells12010098 - 26 Dec 2022

Cited by 10 | Viewed by 2638

Abstract

Neuropathic pain treatment remains a challenging issue because the therapies currently used in the clinic are not sufficiently effective. Moreover, the mechanism of neuropathy is still not entirely understood; however, much evidence indicates that chemokines are important factors in the initial and late phases of neuropathic pain. To date, the roles of CCR1, CCR3 and their endogenous ligands have not been extensively studied; therefore, they have become the subject of our research. In the present comprehensive behavioral and biochemical study, we detected significant time-dependent and long-lasting increases in the mRNA levels of CCR1 and/or CCR3 ligands, such as CCL2/3/4/5/6/7/8/9, in the murine spinal cord after chronic constriction injury of the sciatic nerve, and these increases were accompanied by changes in the levels of microglial/macrophage, astrocyte and neutrophil cell markers. ELISA results suggested that endogenous ligands of CCR1 and CCR3 are involved in the development (CCL2/3/5/7/8/9) and persistence (CCL2/7/8) of neuropathic pain. Moreover, intrathecal injection of CCL2/3/5/7/8/9 confirmed their possible strong influence on mechanical and thermal hypersensitivity development. Importantly, inhibition of CCL2/7/8 production and CCR1 and CCR3 blockade by selective/dual antagonists effectively reduced neuropathic pain-like behavior. The obtained data suggest that CCL2/7/8/CCR1 and CCL7/8/CCR3 signaling are important in the modulation of neuropathic pain in mice and that these chemokines and their receptors may be interesting targets for future investigations. Full article

(This article belongs to the Special Issue The Signaling and Cellular Mechanisms of Pain)

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13 pages, 1871 KiB

Open AccessFeature PaperArticle

RgIA4 Prevention of Acute Oxaliplatin-Induced Cold Allodynia Requires α9-Containing Nicotinic Acetylcholine Receptors and CD3⁺ T-Cells

by Peter N. Huynh, Sean B. Christensen and J. Michael McIntosh

Cells 2022, 11(22), 3561; https://doi.org/10.3390/cells11223561 - 11 Nov 2022

Cited by 13 | Viewed by 2283

Abstract

Chemotherapy-induced neuropathic pain is a debilitating and dose-limiting side effect. Oxaliplatin is a third-generation platinum and antineoplastic compound that is commonly used to treat colorectal cancer and commonly yields neuropathic side effects. Available drugs such as duloxetine provide only modest benefits against oxaliplatin-induced neuropathy. A particularly disruptive symptom of oxaliplatin is painful cold sensitivity, known as cold allodynia. Previous studies of the Conus regius peptide, RgIA, and its analogs have demonstrated relief from oxaliplatin-induced cold allodynia, yielding improvement that persists even after treatment cessation. Moreover, underlying inflammatory and neuronal protection were shown at the cellular level in chronic constriction nerve injury models, consistent with disease-modifying effects. Despite these promising preclinical outcomes, the underlying molecular mechanism of action of RgIA4 remains an area of active investigation. This study aimed to determine the necessity of the α9 nAChR subunit and potential T-cell mechanisms in RgIA4 efficacy against acute oxaliplatin-induced cold allodynia. A single dose of oxaliplatin (10 mg/kg) was utilized followed by four daily doses of RgIA4. Subcutaneous administration of RgIA4 (40 µg/kg) prevented cold allodynia in wildtype mice but not in mice lacking the α9 nAChR-encoding gene, chrna9. RgIA4 also failed to reverse allodynia in mice depleted of CD3⁺ T-cells. In wildtype mice treated with oxaliplatin, quantitated circulating T-cells remained unaffected by RgIA4. Together, these results show that RgIA4 requires both chrna9 and CD3⁺ T-cells to exert its protective effects against acute cold-allodynia produced by oxaliplatin. Full article

(This article belongs to the Special Issue The Signaling and Cellular Mechanisms of Pain)

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Review

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13 pages, 1258 KiB

Open AccessReview

Modulation of Glial Cell Functions by the Gut–Brain Axis: A Role in Neurodegenerative Disorders and Pain Transmission

by Giulia Magni, Benedetta Riboldi and Stefania Ceruti

Cells 2023, 12(12), 1612; https://doi.org/10.3390/cells12121612 - 13 Jun 2023

Cited by 9 | Viewed by 2155

Abstract

Studies on host microbiota and their interactions with the central nervous system (CNS) have grown considerably in the last decade. Indeed, it has been widely demonstrated that dysregulations of the bidirectional gut–brain crosstalk are involved in the development of several pathological conditions, including chronic pain. In addition, the activation of central and peripheral glial cells is also implicated in the pathogenesis and progression of pain and other neurodegenerative disorders. Recent preclinical findings suggest that the gut microbiota plays a pivotal role in regulating glial maturation, morphology and function, possibly through the action of different microbial metabolites, including the most studied short-chain fatty acids (SCFAs). Moreover, altered microbiota composition has been reported in CNS disorders characterized by glial cell activation. In this review, we discuss recent studies showing the role of the gut microbiota and the effects of its depletion in modulating the morphology and function of glial cells (microglia and astrocytes), and we hypothesize a possible role for glia–microbiota interactions in the development and maintenance of chronic pain. Full article

(This article belongs to the Special Issue The Signaling and Cellular Mechanisms of Pain)

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