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Keywords = trigeminal neuron

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14 pages, 2786 KiB  
Article
Local Administration of (−)-Epigallocatechin-3-Gallate as a Local Anesthetic Agent Inhibits the Excitability of Rat Nociceptive Primary Sensory Neurons
by Syogo Utugi, Risako Chida, Sana Yamaguchi, Yukito Sashide and Mamoru Takeda
Cells 2025, 14(1), 52; https://doi.org/10.3390/cells14010052 - 5 Jan 2025
Viewed by 458
Abstract
While the impact of (−)-epigallocatechin-3-gallate (EGCG) on modulating nociceptive secondary neuron activity has been documented, it is still unknown how EGCG affects the excitability of nociceptive primary neurons in vivo. The objective of the current study was to investigate whether administering EGCG locally [...] Read more.
While the impact of (−)-epigallocatechin-3-gallate (EGCG) on modulating nociceptive secondary neuron activity has been documented, it is still unknown how EGCG affects the excitability of nociceptive primary neurons in vivo. The objective of the current study was to investigate whether administering EGCG locally in rats reduces the excitability of nociceptive primary trigeminal ganglion (TG) neurons in response to mechanical stimulation in vivo. In anesthetized rats, TG neuronal extracellular single unit recordings were made in response to both non-noxious and noxious mechanical stimuli. Following the administration of EGCG, the mean firing rate of TG neurons to both non-noxious and noxious mechanical stimuli significantly decreased in a dose-dependent manner (1–10 mM), and both the non-noxious and nociceptive mechanical stimuli experienced the maximum suppression of discharge frequency within 5 min. These inhibitory effects lasted for approximately 20 min. These findings suggest that the local injection of EGCG into the peripheral receptive field suppresses the responsiveness of nociceptive primary sensory neurons in the TG, almost equal to that of the local anesthetic, 1% lidocaine. As a result, the local application of EGCG as a local anesthetic could alleviate nociceptive trigeminal pain that does not result in side effects, thereby playing a significant role in pain management. Full article
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15 pages, 2579 KiB  
Article
Naringenin Suppresses the Hyperexcitability of Trigeminal Nociceptive Neurons Associated with Inflammatory Hyperalgesia: Replacement of NSAIDs with Phytochemicals
by Sora Yajima, Risa Sakata, Yui Watanuki, Yukito Sashide and Mamoru Takeda
Nutrients 2024, 16(22), 3895; https://doi.org/10.3390/nu16223895 - 15 Nov 2024
Viewed by 623
Abstract
The present study examines whether the systemic application of naringenin (NRG) reduces inflammation-induced hyperexcitability in the spinal trigeminal nucleus caudalis (SpVc) related to hyperalgesia, and compares its impact with that of diclofenac (DIC). To provoke inflammation, the whisker pads of rats were injected [...] Read more.
The present study examines whether the systemic application of naringenin (NRG) reduces inflammation-induced hyperexcitability in the spinal trigeminal nucleus caudalis (SpVc) related to hyperalgesia, and compares its impact with that of diclofenac (DIC). To provoke inflammation, the whisker pads of rats were injected with complete Freund’s adjuvant, and subsequently, mechanical stimuli were administered to the orofacial region to determine the escape threshold. Compared to naïve rats, the inflamed rats showed a significantly lower mechanical threshold, and this reduced threshold returned to normal levels two days post-administration of NRG, DIC, and half-dose DIC plus half-dose NRG (1/2 DIC + 1/2 NRG). Using extracellular single-unit recordings, the activity of SpVc wide-dynamic range neurons was measured in response to mechanical stimulation of the orofacial area under anesthesia. The average firing rate of SpVc neurons when exposed to both non-painful and painful mechanical stimuli was significantly reduced in inflamed rats following NRG, DIC, and 1/2 DIC + 1/2 NRG administration. The heightened average spontaneous activity of SpVc neurons in rats with inflammation was significantly reduced following NRG, DIC, and 1/2 DIC + 1/2 NRG administration. The increased average receptive field size observed in inflamed rats reverted to normal levels after either NRG, DIC, or 1/2 DIC + 1/2 NRG treatment. These findings indicate that NRG administration can reduce inflammatory hyperalgesia linked to the heightened excitability of SpVc wide-dynamic range neurons. Full article
(This article belongs to the Section Phytochemicals and Human Health)
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16 pages, 1850 KiB  
Review
Stress Can Induce Bovine Alpha-Herpesvirus 1 (BoHV-1) Reactivation from Latency
by Fouad El-Mayet and Clinton Jones
Viruses 2024, 16(11), 1675; https://doi.org/10.3390/v16111675 - 27 Oct 2024
Viewed by 1281
Abstract
Bovine alpha-herpesvirus 1 (BoHV-1) is a significant problem for the cattle industry, in part because the virus establishes latency, and stressful stimuli increase the incidence of reactivation from latency. Sensory neurons in trigeminal ganglia and unknown cells in pharyngeal tonsils are important
sites [...] Read more.
Bovine alpha-herpesvirus 1 (BoHV-1) is a significant problem for the cattle industry, in part because the virus establishes latency, and stressful stimuli increase the incidence of reactivation from latency. Sensory neurons in trigeminal ganglia and unknown cells in pharyngeal tonsils are important
sites for latency. Reactivation from latency can lead to reproductive problems in pregnant cows, virus transmission to young calves, suppression of immune responses, and bacterial pneumonia. BoHV-1 is also a significant cofactor in bovine respiratory disease (BRD). Stress, as mimicked by the synthetic corticosteroid dexamethasone, reproducibly initiates reactivation from latency. Stress-mediated activation of the glucocorticoid receptor (GR) stimulates viral replication and transactivation of viral promoters that drive the expression of infected cell protein 0 (bICP0) and bICP4. Notably, GR and Krüppel-like factor 15 (KLF15) form a feed-forward transcription loop that cooperatively transactivates immediate early transcription unit 1 (IEtu1 promoter). Two  pioneer transcription factors, GR and KLF4, cooperatively transactivate the bICP0 early promoter. Pioneer transcription factors bind silent viral  heterochromatin, remodel chromatin, and activate gene expression. Thus, we
predict that these novel transcription factors mediate early stages of BoHV-1 reactivation from latency. Full article
(This article belongs to the Special Issue Herpesvirus Latency 2024)
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14 pages, 1420 KiB  
Review
Molecular and Cellular Neurobiology of Spreading Depolarization/Depression and Migraine: A Narrative Review
by Eiji Kitamura and Noboru Imai
Int. J. Mol. Sci. 2024, 25(20), 11163; https://doi.org/10.3390/ijms252011163 - 17 Oct 2024
Viewed by 1407
Abstract
Migraine is a prevalent neurological disorder, particularly among individuals aged 20–50 years, with significant social and economic impacts. Despite its high prevalence, the pathogenesis of migraine remains unclear. In this review, we provide a comprehensive overview of cortical spreading depolarization/depression (CSD) and its [...] Read more.
Migraine is a prevalent neurological disorder, particularly among individuals aged 20–50 years, with significant social and economic impacts. Despite its high prevalence, the pathogenesis of migraine remains unclear. In this review, we provide a comprehensive overview of cortical spreading depolarization/depression (CSD) and its close association with migraine aura, focusing on its role in understanding migraine pathogenesis and therapeutic interventions. We discuss historical studies that have demonstrated the role of CSD in the visual phenomenon of migraine aura, along with modern imaging techniques confirming its propagation across the occipital cortex. Animal studies are examined to indicate that CSD is not exclusive to migraines; it also occurs in other neurological conditions. At the cellular level, we review how CSD is characterized by ionic changes and excitotoxicity, leading to neuronal and glial responses. We explore how CSD activates the trigeminal nervous system and upregulates the expression of calcitonin gene-related peptides (CGRP), thereby contributing to migraine pain. Factors such as genetics, obesity, and environmental conditions that influence the CSD threshold are discussed, suggesting potential therapeutic targets. Current treatments for migraine, including prophylactic agents and CGRP-targeting drugs, are evaluated in the context of their expected effects on suppressing CSD activity. Additionally, we highlight emerging therapies such as intranasal insulin-like growth factor 1 and vagus nerve stimulation, which have shown promise in reducing CSD susceptibility and frequency. By elucidating the molecular and cellular mechanisms of CSD, this review aims to enhance the understanding of migraine pathogenesis and support the development of targeted therapeutic strategies. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Treatment of Migraine)
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16 pages, 4417 KiB  
Article
A Quadruple Gene-Deleted Live BoHV-1 Subunit RVFV Vaccine Vector Reactivates from Latency and Replicates in the TG Neurons of Calves but Is Not Transported to and Shed from Nasal Mucosa
by Selvaraj Pavulraj, Rhett W. Stout, Daniel B. Paulsen and Shafiqul I. Chowdhury
Viruses 2024, 16(9), 1497; https://doi.org/10.3390/v16091497 - 21 Sep 2024
Viewed by 1414
Abstract
Bovine herpesvirus type 1 (BoHV-1) establishes lifelong latency in trigeminal ganglionic (TG) neurons following intranasal and ocular infection in cattle. Periodically, the latent virus reactivates in the TG due to stress and is transported anterogradely to nerve endings in the nasal epithelium, where [...] Read more.
Bovine herpesvirus type 1 (BoHV-1) establishes lifelong latency in trigeminal ganglionic (TG) neurons following intranasal and ocular infection in cattle. Periodically, the latent virus reactivates in the TG due to stress and is transported anterogradely to nerve endings in the nasal epithelium, where the virus replicates and sheds. Consequently, BoHV-1 is transmitted to susceptible animals and maintained in the cattle population. Modified live BoHV-1 vaccine strains (BoHV-1 MLV) also have a similar latency reactivation. Therefore, they circulate and are maintained in cattle herds. Additionally, they can regain virulence and cause vaccine outbreaks because they mutate and recombine with other circulating field wild-type (wt) strains. Recently, we constructed a BoHV-1 quadruple mutant virus (BoHV-1qmv) that lacks immune evasive properties due to UL49.5 and glycoprotein G (gG) deletions. In addition, it also lacks the gE cytoplasmic tail (gE CT) and Us9 gene sequences designed to make it safe, increase its vaccine efficacy against BoHV-1, and restrict its anterograde neuronal transport noted above. Further, we engineered the BoHV-1qmv-vector to serve as a subunit vaccine against the Rift Valley fever virus (BoHV-1qmv Sub-RVFV) (doi: 10.3390/v15112183). In this study, we determined the latency reactivation and nasal virus shedding properties of BoHV-1qmv (vector) and BoHV-1qmv-vectored subunit RVFV (BoHV-1qmv sub-RVFV) vaccine virus in calves in comparison to the BoHV-1 wild-type (wt) following intranasal inoculation. The real-time PCR results showed that BoHV-1 wt- but not the BoHV-1qmv vector- and BoHV-1qmv Sub-RVFV-inoculated calves shed virus in the nose following dexamethasone-induced latency reactivation; however, like the BoHV-1 wt, both the BoHV-1qmv vector and BoHV-1qmv Sub-RVFV viruses established latency, were reactivated, and replicated in the TG neurons. These results are consistent with the anterograde neurotransport function of the gE CT and Us9 sequences, which are deleted in the BoHV-1qmv and BoHV-1qmv Sub-RVFV. Full article
(This article belongs to the Section Animal Viruses)
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11 pages, 2556 KiB  
Article
Suppression of the Excitability of Nociceptive Secondary Sensory Neurons Following Systemic Administration of Astaxanthin in Rats
by Risako Chida, Sana Yamaguchi, Syogo Utugi, Yukito Sashide and Mamoru Takeda
Anesth. Res. 2024, 1(2), 117-127; https://doi.org/10.3390/anesthres1020012 - 2 Sep 2024
Viewed by 711
Abstract
Although astaxanthin (AST) has demonstrated a modulatory effect on voltage-gated Ca2+ (Cav) channels and excitatory glutamate neuronal transmission in vitro, particularly on the excitability of nociceptive sensory neurons, its action in vivo remains to be determined. This research sought to determine if [...] Read more.
Although astaxanthin (AST) has demonstrated a modulatory effect on voltage-gated Ca2+ (Cav) channels and excitatory glutamate neuronal transmission in vitro, particularly on the excitability of nociceptive sensory neurons, its action in vivo remains to be determined. This research sought to determine if an acute intravenous administration of AST in rats reduces the excitability of wide-dynamic range (WDR) spinal trigeminal nucleus caudalis (SpVc) neurons in response to nociceptive and non-nociceptive mechanical stimulation in vivo. In anesthetized rats, extracellular single-unit recordings were carried out on SpVc neurons following mechanical stimulation of the orofacial area. The average firing rate of SpVc WDR neurons in response to both gentle and painful mechanical stimuli significantly and dose-dependently decreased after the application of AST (1–5 mM, i.v.), and maximum suppression of discharge frequency for both non-noxious and nociceptive mechanical stimuli occurred within 10 min. These suppressive effects persisted for about 20 min. These results suggest that acute intravenous AST administration suppresses the SpVc nociceptive transmission, possibly by inhibiting Cav channels and excitatory glutamate neuronal transmission, implicating AST as a potential therapeutic agent for the treatment of trigeminal nociceptive pain without side effects. Full article
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13 pages, 1279 KiB  
Review
The Phytochemical, Quercetin, Attenuates Nociceptive and Pathological Pain: Neurophysiological Mechanisms and Therapeutic Potential
by Mamoru Takeda, Yukito Sashide, Ryou Toyota and Haruka Ito
Molecules 2024, 29(16), 3957; https://doi.org/10.3390/molecules29163957 - 21 Aug 2024
Cited by 3 | Viewed by 1471
Abstract
Although phytochemicals are plant-derived toxins that are primarily produced as a form of defense against insects or microbes, several lines of study have demonstrated that the phytochemical, quercetin, has several beneficial biological actions for human health, including antioxidant and inflammatory effects without side [...] Read more.
Although phytochemicals are plant-derived toxins that are primarily produced as a form of defense against insects or microbes, several lines of study have demonstrated that the phytochemical, quercetin, has several beneficial biological actions for human health, including antioxidant and inflammatory effects without side effects. Quercetin is a flavonoid that is widely found in fruits and vegetables. Since recent studies have demonstrated that quercetin can modulate neuronal excitability in the nervous system, including nociceptive sensory transmission via mechanoreceptors and voltage-gated ion channels, and inhibit the cyclooxygenase-2-cascade, it is possible that quercetin could be a complementary alternative medicine candidate; specifically, a therapeutic agent against nociceptive and pathological pain. The focus of this review is to elucidate the neurophysiological mechanisms underlying the modulatory effects of quercetin on nociceptive neuronal activity under nociceptive and pathological conditions, without inducing side effects. Based on the results of our previous research on trigeminal pain, we have confirmed in vivo that the phytochemical, quercetin, demonstrates (i) a local anesthetic effect on nociceptive pain, (ii) a local anesthetic effect on pain related to acute inflammation, and (iii) an anti-inflammatory effect on chronic pain. In addition, we discuss the contribution of quercetin to the relief of nociceptive and inflammatory pain and its potential clinical application. Full article
(This article belongs to the Special Issue Bioactive Phenolic and Polyphenolic Compounds, Volume III)
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11 pages, 2174 KiB  
Article
KCNG4 Genetic Variant Linked to Migraine Prevents Expression of KCNB1
by Gabriel Lacroix, Shreyas Bhat, Zerghona Shafia and Rikard Blunck
Int. J. Mol. Sci. 2024, 25(16), 8960; https://doi.org/10.3390/ijms25168960 - 17 Aug 2024
Viewed by 852
Abstract
Migraines are a common type of headache affecting around 15% of the population. The signalling pathways leading to migraines have not been fully understood, but neuronal voltage-gated ion channels, such as KCNG4, have been linked to this pathology. KCNG4 (Kv6.4) is a silent [...] Read more.
Migraines are a common type of headache affecting around 15% of the population. The signalling pathways leading to migraines have not been fully understood, but neuronal voltage-gated ion channels, such as KCNG4, have been linked to this pathology. KCNG4 (Kv6.4) is a silent member of the superfamily of voltage-gated potassium (Kv) channels, which expresses in heterotetramers with members of the KCNB (Kv2) family. The genetic variant Kv6.4-L360P has previously been linked to migraines, but their mode of action remains unknown. Here, we characterized the molecular characteristics of Kv6.4-L360P when co-expressed with Kv2.1. We found that Kv6.4-L360P almost completely abolishes Kv2 currents, and we propose that this mechanism in the trigeminal system, linked to the initiation of migraine, leads to the pathology. Full article
(This article belongs to the Section Molecular Biophysics)
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14 pages, 7554 KiB  
Article
Oxytocin Receptors on Calvarial Periosteal Innervation: Therapeutic Target for Post-Traumatic Headache?
by Vimala N. Bharadwaj, Michael Klukinov, Robert Paul Cowan, Nazanin Mahinparvar, David John Clark and David Clifford Yeomans
Pharmaceutics 2024, 16(6), 760; https://doi.org/10.3390/pharmaceutics16060760 - 4 Jun 2024
Viewed by 938
Abstract
Objective: Following a mild traumatic brain injury (mTBI), the most prevalent and profoundly debilitating occurrence is the emergence of an acute and persistent post-traumatic headache (PTH), for which there are presently no approved treatments. A crucial gap in knowledge exists regarding the consequences [...] Read more.
Objective: Following a mild traumatic brain injury (mTBI), the most prevalent and profoundly debilitating occurrence is the emergence of an acute and persistent post-traumatic headache (PTH), for which there are presently no approved treatments. A crucial gap in knowledge exists regarding the consequences of an mTBI, which could serve as a foundation for the development of therapeutic approaches. The activation of trigeminal sensory nerve terminals that innervate the calvarial periosteum (CP)—a densely innervated tissue layer covering the calvarial skull—has been implicated in both migraines and PTHs. We have previously shown that trigeminal oxytocin receptors (OTRs) may provide a therapeutic target for PTHs. This study examined the expression of oxytocin receptors on trigeminal nerves innervating the periosteum and whether these receptors might serve as a therapeutic target for PTHs using a direct application of oxytocin to the periosteum in a rodent model of PTH. Methods: We used retrograde tracing and immunohistochemistry to determine if trigeminal ganglion (TG) neurons innervating the periosteum expressed OTRs and/or CGRPs. To model the impact of local inflammation that occurs following an mTBI, we applied chemical inflammatory mediators directly to the CP and assessed for changes in immediate-early gene expression as an indication of neuronal activation. We also determined whether mTBI would lead to expression changes to OTR levels. To determine whether these OTRs could be a viable therapeutic target, we assessed the impact of oxytocin injections into the CP in a mouse model of PTH-induced periorbital allodynia. Results: The results of these experiments demonstrate the following: (1) the cell bodies of CP afferents reside in the TG and express both OTRs and CGRPs; (2) inflammatory chemical stimulation of the periosteum leads to rapid activation of TG neurons (phospho-ERK (p-ERK) expression), (3) mTBI-induced inflammation increased OTR expression compared to the sham group; and (4) administration of oxytocin into the periosteum on day 2 and day 40 blocked cutaneous allodynia for up to one hour post-administration for both acute and persistence phases in the PTH model—an effect that was preventable by the administration of an OTR antagonist. Conclusion: Taken together, our observations suggest that periosteal trigeminal afferents contribute to post-TBI craniofacial pain, and that periosteum tissue can be used as a potential local target for therapeutics such as oxytocin. Full article
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18 pages, 12857 KiB  
Article
Dynamics of Cellular Regulation of Fractalkine/CX3CL1 and Its Receptor CX3CR1 in the Rat Trigeminal Subnucleus Caudalis after Unilateral Infraorbital Nerve Lesion—Extended Cellular Signaling of the CX3CL1/CX3CR1 Axis in the Development of Trigeminal Neuropathic Pain
by Lucie Kubíčková and Petr Dubový
Int. J. Mol. Sci. 2024, 25(11), 6069; https://doi.org/10.3390/ijms25116069 - 31 May 2024
Cited by 2 | Viewed by 868
Abstract
The cellular distribution and changes in CX3CL1/fractalkine and its receptor CX3CR1 protein levels in the trigeminal subnucleus caudalis (TSC) of rats with unilateral infraorbital nerve ligation (IONL) were investigated on postoperation days 1, 3, 7, and 14 (POD1, POD3, POD7, and POD14, respectively) [...] Read more.
The cellular distribution and changes in CX3CL1/fractalkine and its receptor CX3CR1 protein levels in the trigeminal subnucleus caudalis (TSC) of rats with unilateral infraorbital nerve ligation (IONL) were investigated on postoperation days 1, 3, 7, and 14 (POD1, POD3, POD7, and POD14, respectively) and compared with those of sham-operated and naïve controls. Behavioral tests revealed a significant increase in tactile hypersensitivity bilaterally in the vibrissal pads of both sham- and IONL-operated animals from POD1 to POD7, with a trend towards normalization in sham controls at POD14. Image analysis revealed increased CX3CL1 immunofluorescence (IF) intensities bilaterally in the TSC neurons of both sham- and IONL-operated rats at all survival periods. Reactive astrocytes in the ipsilateral TSC also displayed CX3CL1-IF from POD3 to POD14. At POD1 and POD3, microglial cells showed high levels of CX3CR1-IF, which decreased by POD7 and POD14. Conversely, CX3CR1 was increased in TSC neurons and reactive astrocytes at POD7 and POD14, which coincided with high levels of CX3CL1-IF and ADAM17-IF. This indicates that CX3CL1/CX3CR1 may be involved in reciprocal signaling between TSC neurons and reactive astrocytes. The level of CatS-IF in microglial cells suggests that soluble CX3CL1 may be involved in neuron–microglial cell signaling at POD3 and POD7, while ADAM17 allows this release at all studied time points. These results indicate an extended CX3CL1/CX3CR1 signaling axis and its role in the crosstalk between TSC neurons and glial cells during the development of trigeminal neuropathic pain. Full article
(This article belongs to the Special Issue The Multiple Mechanisms Underlying Neuropathic Pain (III))
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18 pages, 4802 KiB  
Article
Subarachnoid Hemorrhage Depletes Calcitonin Gene-Related Peptide Levels of Trigeminal Neurons in Rat Dura Mater
by Thannoon Masood, Szandra Lakatos, Gyöngyi Kis, Melissza Ignácz, Ferenc Domoki and Judit Rosta
Cells 2024, 13(8), 653; https://doi.org/10.3390/cells13080653 - 9 Apr 2024
Cited by 1 | Viewed by 1267
Abstract
Subarachnoid hemorrhage (SAH) remains a major cause of cerebrovascular morbidity, eliciting severe headaches and vasospasms that have been shown to inversely correlate with vasodilator calcitonin gene-related peptide (CGRP) levels. Although dura mater trigeminal afferents are an important source of intracranial CGRP, little is [...] Read more.
Subarachnoid hemorrhage (SAH) remains a major cause of cerebrovascular morbidity, eliciting severe headaches and vasospasms that have been shown to inversely correlate with vasodilator calcitonin gene-related peptide (CGRP) levels. Although dura mater trigeminal afferents are an important source of intracranial CGRP, little is known about the effects of SAH on these neurons in preclinical models. The present study evaluated changes in CGRP levels and expression in trigeminal primary afferents innervating the dura mater 72 h after experimentally induced SAH in adult rats. SAH, eliciting marked damage revealed by neurological examination, significantly reduced the density of CGRP-immunoreactive nerve fibers both in the dura mater and the trigeminal caudal nucleus in the medulla but did not affect the total dural nerve fiber density. SAH attenuated ex vivo dural CGRP release by ~40% and in the trigeminal ganglion, reduced both CGRP mRNA levels and the number of highly CGRP-immunoreactive cell bodies. In summary, we provide novel complementary evidence that SAH negatively affects the integrity of the CGRP-expressing rat trigeminal neurons. Reduced CGRP levels suggest likely impaired meningeal neurovascular functions contributing to SAH complications. Further studies are to be performed to reveal the importance of impaired CGRP synthesis and its consequences in central sensory processing. Full article
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21 pages, 4220 KiB  
Review
Satellite Glial Cells in Human Disease
by Menachem Hanani
Cells 2024, 13(7), 566; https://doi.org/10.3390/cells13070566 - 23 Mar 2024
Cited by 2 | Viewed by 3215
Abstract
Satellite glial cells (SGCs) are the main type of glial cells in sensory ganglia. Animal studies have shown that these cells play essential roles in both normal and disease states. In a large number of pain models, SGCs were activated and contributed to [...] Read more.
Satellite glial cells (SGCs) are the main type of glial cells in sensory ganglia. Animal studies have shown that these cells play essential roles in both normal and disease states. In a large number of pain models, SGCs were activated and contributed to the pain behavior. Much less is known about SGCs in humans, but there is emerging recognition that SGCs in humans are altered in a variety of clinical states. The available data show that human SGCs share some essential features with SGCs in rodents, but many differences do exist. SGCs in DRG from patients suffering from common painful diseases, such as rheumatoid arthritis and fibromyalgia, may contribute to the pain phenotype. It was found that immunoglobulins G (IgG) from fibromyalgia patients can induce pain-like behavior in mice. Moreover, these IgGs bind preferentially to SGCs and activate them, which can sensitize the sensory neurons, causing nociception. In other human diseases, the evidence is not as direct as in fibromyalgia, but it has been found that an antibody from a patient with rheumatoid arthritis binds to mouse SGCs, which leads to the release of pronociceptive factors from them. Herpes zoster is another painful disease, and it appears that the zoster virus resides in SGCs, which acquire an abnormal morphology and may participate in the infection and pain generation. More work needs to be undertaken on SGCs in humans, and this review points to several promising avenues for better understanding disease mechanisms and developing effective pain therapies. Full article
(This article belongs to the Special Issue Emerging Roles of Glial Cells in Human Health and Disease)
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19 pages, 15893 KiB  
Article
Immunocytochemical Analysis of Crocin against Oxidative Stress in Trigeminal Sensory Neurons Innervating the Cornea
by Cristina Sánchez-Fernández, Susana Del Olmo-Aguado, Enol Artime, Alberto Barros, Luis Fernández-Vega Cueto, Jesús Merayo-Lloves and Ignacio Alcalde
Molecules 2024, 29(2), 456; https://doi.org/10.3390/molecules29020456 - 17 Jan 2024
Viewed by 1421
Abstract
Corneal diseases are a major cause of vision loss, often associated with aging, trauma and disease. Damage to corneal sensory innervation leads to discomfort and pain. Environmental stressors, such as short-wavelength light, can induce oxidative stress that alters mitochondrial function and affects cell [...] Read more.
Corneal diseases are a major cause of vision loss, often associated with aging, trauma and disease. Damage to corneal sensory innervation leads to discomfort and pain. Environmental stressors, such as short-wavelength light, can induce oxidative stress that alters mitochondrial function and affects cell and tissue homeostasis, including corneal innervation. Cellular antioxidant mechanisms may attenuate oxidative stress. This study investigates crocin, a derivative of saffron, as a potential antioxidant therapy. In vitro rat trigeminal sensory ganglion neurons were exposed to both sodium azide and blue light overexposure as a model of oxidative damage. Crocin was used as a neuroprotective agent. Mitochondrial and cytoskeletal markers were studied by immunofluorescence analysis to determine oxidative damage and neuroprotection. In vivo corneal innervation degeneration was evaluated in cornea whole mount preparations using Sholl analyses. Blue light exposure induces oxidative stress that affects trigeminal neuron mitochondria and alters sensory axon dynamics in vitro, and it also affects corneal sensory innervation in an in vivo model. Our results show that crocin was effective in preserving mitochondrial function and protecting corneal sensory neurons from oxidative stress. Crocin appears to be a promising candidate for the neuroprotection of corneal innervation. Full article
(This article belongs to the Special Issue Study on the Bioactive Compounds from Plant Extraction)
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14 pages, 2563 KiB  
Article
Differential Regulation of Intracisternally Injected Angiotensin II-Induced Mechanical Allodynia and Thermal Hyperalgesia in Rats
by Ki-Don Park, Jo-Young Son, Hak-Kyun Kim, Yu-Mi Kim, Jin-Sook Ju, Min-Jeong Jo, Min-Kyoung Park, Min-Kyung Lee and Dong-Kuk Ahn
Biomedicines 2023, 11(12), 3279; https://doi.org/10.3390/biomedicines11123279 - 12 Dec 2023
Viewed by 1345
Abstract
The present study examined the underlying mechanisms of mechanical allodynia and thermal hyperalgesia induced by the intracisternal injection of angiotensin (Ang) II. Intracisternal Ang II injection decreased the air puff threshold and head withdrawal latency. To determine the operative receptors for each distinct [...] Read more.
The present study examined the underlying mechanisms of mechanical allodynia and thermal hyperalgesia induced by the intracisternal injection of angiotensin (Ang) II. Intracisternal Ang II injection decreased the air puff threshold and head withdrawal latency. To determine the operative receptors for each distinct type of pain behavior, we intracisternally injected Ang II receptor antagonists 2 h after Ang II injection. Losartan, an Ang II type 1 receptor (AT1R) antagonist, alleviated mechanical allodynia. Conversely, PD123319, an Ang II type 1 receptor (AT2R) antagonist, blocked only thermal hyperalgesia. Immunofluorescence analyses revealed the co-localization of AT1R with the astrocyte marker GFAP in the trigeminal subnucleus caudalis and co-localization of AT2R with CGRP-positive neurons in the trigeminal ganglion. Intracisternal pretreatment with minocycline, a microglial inhibitor, did not affect Ang II-induced mechanical allodynia, whereas L-α-aminoadipate, an astrocyte inhibitor, significantly inhibited Ang II-induced mechanical allodynia. Furthermore, subcutaneous pretreatment with botulinum toxin type A significantly alleviated Ang II-induced thermal hyperalgesia, but not Ang II-induced mechanical allodynia. These results indicate that central Ang II-induced nociception is differentially regulated by AT1R and AT2R. Thus, distinct therapeutic targets must be regulated to overcome pain symptoms caused by multiple underlying mechanisms. Full article
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22 pages, 11814 KiB  
Article
Dopaminergic Projections from the Hypothalamic A11 Nucleus to the Spinal Trigeminal Nucleus Are Involved in Bidirectional Migraine Modulation
by Chenhao Li, Yang Li, Wenwen Zhang, Zhenjie Ma, Shaobo Xiao, Wei Xie, Shuai Miao, Bozhi Li, Guangshuang Lu, Yingyuan Liu, Wenhao Bai and Shengyuan Yu
Int. J. Mol. Sci. 2023, 24(23), 16876; https://doi.org/10.3390/ijms242316876 - 28 Nov 2023
Cited by 1 | Viewed by 1995
Abstract
Clinical imaging studies have revealed that the hypothalamus is activated in migraine patients prior to the onset of and during headache and have also shown that the hypothalamus has increased functional connectivity with the spinal trigeminal nucleus. The dopaminergic system of the hypothalamus [...] Read more.
Clinical imaging studies have revealed that the hypothalamus is activated in migraine patients prior to the onset of and during headache and have also shown that the hypothalamus has increased functional connectivity with the spinal trigeminal nucleus. The dopaminergic system of the hypothalamus plays an important role, and the dopamine-rich A11 nucleus may play an important role in migraine pathogenesis. We used intraperitoneal injections of glyceryl trinitrate to establish a model of acute migraine attack and chronicity in mice, which was verified by photophobia experiments and von Frey experiments. We explored the A11 nucleus and its downstream pathway using immunohistochemical staining and neuronal tracing techniques. During acute migraine attack and chronification, c-fos expression in GABAergic neurons in the A11 nucleus was significantly increased, and inhibition of DA neurons was achieved by binding to GABA A-type receptors on the surface of dopaminergic neurons in the A11 nucleus. However, the expression of tyrosine hydroxylase and glutamic acid decarboxylase proteins in the A11 nucleus of the hypothalamus did not change significantly. Specific destruction of dopaminergic neurons in the A11 nucleus of mice resulted in severe nociceptive sensitization and photophobic behavior. The expression levels of the D1 dopamine receptor and D2 dopamine receptor in the caudal part of the spinal trigeminal nucleus candalis of the chronic migraine model were increased. Skin nociceptive sensitization of mice was slowed by activation of the D2 dopamine receptor in SP5C, and activation of the D1 dopamine receptor reversed this behavioral change. GABAergic neurons in the A11 nucleus were activated and exerted postsynaptic inhibitory effects, which led to a decrease in the amount of DA secreted by the A11 nucleus in the spinal trigeminal nucleus candalis. The reduced DA bound preferentially to the D2 dopamine receptor, thus exerting a defensive effect against headache. Full article
(This article belongs to the Special Issue Molecular and Cellular Neurobiology of Migraine: 2nd Edition)
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