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Military Medical Research Apr 2024The channel-forming protein Pannexin1 (Panx1) has been implicated in both human studies and animal models of chronic pain, but the underlying mechanisms remain...
BACKGROUND
The channel-forming protein Pannexin1 (Panx1) has been implicated in both human studies and animal models of chronic pain, but the underlying mechanisms remain incompletely understood.
METHODS
Wild-type (WT, n = 24), global Panx1 KO (n = 24), neuron-specific Panx1 KO (n = 20), and glia-specific Panx1 KO (n = 20) mice were used in this study at Albert Einstein College of Medicine. The von Frey test was used to quantify pain sensitivity in these mice following complete Freund's adjuvant (CFA) injection (7, 14, and 21 d). The qRT-PCR was employed to measure mRNA levels of Panx1, Panx2, Panx3, Cx43, Calhm1, and β-catenin. Laser scanning confocal microscopy imaging, Sholl analysis, and electrophysiology were utilized to evaluate the impact of Panx1 on neuronal excitability and morphology in Neuro2a and dorsal root ganglion neurons (DRGNs) in which Panx1 expression or function was manipulated. Ethidium bromide (EtBr) dye uptake assay and calcium imaging were employed to investigate the role of Panx1 in adenosine triphosphate (ATP) sensitivity. β-galactosidase (β-gal) staining was applied to determine the relative cellular expression levels of Panx1 in trigeminal ganglia (TG) and DRG of transgenic mice.
RESULTS
Global or neuron-specific Panx1 deletion markedly decreased pain thresholds after CFA stimuli (7, 14, and 21 d; P < 0.01 vs. WT group), indicating that Panx1 was positively correlated with pain sensitivity. In Neuro2a, global Panx1 deletion dramatically reduced neurite extension and inward currents compared to the WT group (P < 0.05), revealing that Panx1 enhanced neurogenesis and excitability. Similarly, global Panx1 deletion significantly suppressed Wnt/β-catenin dependent DRG neurogenesis following 5 d of nerve growth factor (NGF) treatment (P < 0.01 vs. WT group). Moreover, Panx1 channels enhanced DRG neuron response to ATP after CFA injection (P < 0.01 vs. Panx1 KO group). Furthermore, ATP release increased Ca responses in DRGNs and satellite glial cells surrounding them following 7 d of CFA treatment (P < 0.01 vs. Panx1 KO group), suggesting that Panx1 in glia also impacts exaggerated neuronal excitability. Interestingly, neuron-specific Panx1 deletion was found to markedly reduce differentiation in cultured DRGNs, as evidenced by stunted neurite outgrowth (P < 0.05 vs. Panx1 KO group; P < 0.01 vs. WT group or GFAP-Cre group), blunted activation of Wnt/β-catenin signaling (P < 0.01 vs. WT, Panx1 KO and GFAP-Cre groups), and diminished cell excitability (P < 0.01 vs. GFAP-Cre group) and response to ATP stimulation (P < 0.01 vs. WT group). Analysis of β-gal staining showed that cellular expression levels of Panx1 in neurons are significantly higher (2.5-fold increase) in the DRG than in the TG.
CONCLUSIONS
The present study revealed that neuronal Panx1 is a prominent driver of peripheral sensitivity in the setting of inflammatory pain through cell-autonomous effects on neuronal excitability. This hyperexcitability dependence on neuronal Panx1 contrasts with inflammatory orofacial pain, where similar studies revealed a prominent role for glial Panx1. The apparent differences in Panx1 expression in neuronal and non-neuronal TG and DRG cells are likely responsible for the distinct impact of these cell types in the two pain models.
Topics: Animals; Connexins; Mice; Nerve Tissue Proteins; Disease Models, Animal; Pain; Neurons; Inflammation; Mice, Knockout; Male
PubMed: 38685116
DOI: 10.1186/s40779-024-00525-8 -
Brain Sciences Mar 2024Migraine, recognized as a severe headache disorder, is widely prevalent, significantly impacting the quality of life for those affected. This article aims to provide a... (Review)
Review
Migraine, recognized as a severe headache disorder, is widely prevalent, significantly impacting the quality of life for those affected. This article aims to provide a comprehensive review of the application of animal model technologies in unraveling the pathomechanism of migraine and developing more effective therapies. It introduces a variety of animal experimental models used in migraine research, emphasizing their versatility and importance in simulating various aspects of the condition. It details the benefits arising from the utilization of these models, emphasizing their role in elucidating pain mechanisms, clarifying trigeminal activation, as well as replicating migraine symptoms and histological changes. In addition, the article consciously acknowledges the inherent limitations and challenges associated with the application of animal experimental models. Recognizing these constraints is a fundamental step toward fine-tuning and optimizing the models for a more accurate reflection of and translatability to the human environment. Overall, a detailed and comprehensive understanding of migraine animal models is crucial for navigating the complexity of the disease. These findings not only provide a deeper insight into the multifaceted nature of migraine but also serve as a foundation for developing effective therapeutic strategies that specifically address the unique challenges arising from migraine pathology.
PubMed: 38671969
DOI: 10.3390/brainsci14040317 -
Cells Apr 2024Subarachnoid hemorrhage (SAH) remains a major cause of cerebrovascular morbidity, eliciting severe headaches and vasospasms that have been shown to inversely correlate...
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.
Topics: Animals; Calcitonin Gene-Related Peptide; Dura Mater; Male; Rats; Subarachnoid Hemorrhage; Neurons; Rats, Sprague-Dawley; Trigeminal Ganglion; RNA, Messenger; Trigeminal Nerve
PubMed: 38667268
DOI: 10.3390/cells13080653 -
Pain and Therapy Jun 2024Ganglionic local opioid analgesia (GLOA) at the superior cervical ganglion (SCG) is performed for pain control and is known to be an effective procedure. In this study,...
INTRODUCTION
Ganglionic local opioid analgesia (GLOA) at the superior cervical ganglion (SCG) is performed for pain control and is known to be an effective procedure. In this study, we evaluated the spread of the injectate in the area of the SCG. Our expectation was that there would be a correlation between the area and volume of the injectate spread and post-procedural outcome measures.
METHODS
This was a retrospective blinded review of magnetic resonance imaging (MRI) scans. Assessors evaluated the anatomical area of fluid spread, the furthermost spread from midline, any hampered spread and contact of contrast fluid with other structures. The efficacy of GLOA and complications were estimated.
RESULTS
The main solution spread reached from the C1 to C3 vertebrae. The furthest spread in the lateral and sagittal planes was 21.2 and 15.2 mm, respectively. The furthest craniocaudal spread was 63.5 mm. In 53.3% and 33% of interventions, the solution was found in the parapharyngeal space and in its "medial compartment," respectively. A correlation was found between pain relief and both solution spread and volume of solution spread. No hampered spread was recorded. A negative correlation between pain reduction and number of GLOA was observed. Higher pre-procedural pain intensity was correlated with higher pain reduction. We estimated pain relief in 93% of procedures correctly. No correlation between post-procedural Numerical Rating Scale (NRS) scores and different needle approaches was found.
CONCLUSION
For the transoral blocking technique, a strict laterodorsal needle direction is recommended to prevent possible block failures. A total volume of 2 ml injected into the parapharyngeal space and its "medial compartment" is recommended. Higher volumes may lead to uncontrolled distribution patterns.
TRIAL REGISTRATION
Clinicaltrials.gov identifier NCT05257655; date of registration 2022-02-25; patient enrollment date from 2023-01-09 to 2023-08-31.
PubMed: 38662320
DOI: 10.1007/s40122-024-00596-4 -
Cureus Mar 2024Epstein-Barr virus (EBV) can cause follicular conjunctivitis, keratitis, oculoglandular syndrome, meningitis, and encephalitis. We report a 54-year-old Hispanic male who...
Epstein-Barr virus (EBV) can cause follicular conjunctivitis, keratitis, oculoglandular syndrome, meningitis, and encephalitis. We report a 54-year-old Hispanic male who presented with right pupil-involved complete ophthalmoplegia, orbital and masticatory muscle inflammation, trigeminal enhancement, and new corneal infiltrate highly suggestive of EBV. Labwork was negative except for positive EBV polymerase chain reaction (PCR) in serum. Magnetic resonance imaging (MRI) of his brain and orbits with contrast showed enhancement of the right ganglion of the trigeminal nerve, oculomotor nerve, all extraocular muscles in the right orbit, and right masticatory and temporalis muscles and a right subacute lacunar infarct. The patient was diagnosed with encephalitis and orbital-face inflammation secondary to EBV infection. The patient improved with systemic steroids.
PubMed: 38659504
DOI: 10.7759/cureus.56888 -
Scientific Reports Apr 2024Magnetic resonance-diffusion tensor imaging (MR-DTI) has been used in the microvascular decompression and gamma knife radiosurgery in trigeminal neuralgia (TN) patients;...
Magnetic resonance-diffusion tensor imaging (MR-DTI) has been used in the microvascular decompression and gamma knife radiosurgery in trigeminal neuralgia (TN) patients; however, use of percutaneous stereotactic radiofrequency rhizotomy (PSR) to target an abnormal trigeminal ganglion (ab-TG) is unreported. Fractional anisotropy (FA), mean and radial diffusivity (MD and RD, respectively), and axial diffusivity (AD) of the trigeminal nerve (CNV) were measured in 20 TN patients and 40 healthy control participants immediately post PSR, at 6-months, and at 1 year. Longitudinal alteration of the diffusivity metrics and any correlation with treatment effects, or prognoses, were analyzed. In the TN group, either low FA (value < 0.30) or a decreased range compared to the adjacent FA (dFA) > 17% defined an ab-TG. Two-to-three days post PSR, all 15 patients reported decreased pain scores with increased FA at the ab-TG (P < 0.001), but decreased MD and RD (P < 0.01 each). Treatment remained effective in 10 of 14 patients (71.4%) and 8 of 12 patients (66.7%) at the 6-month and 1-year follow-ups, respectively. In patients with ab-TGs, there was a significant difference in treatment outcomes between patients with low FA values (9 of 10; 90%) and patients with dFA (2 of 5; 40%) (P < 0.05). MR-DTI with diffusivity metrics correlated microstructural CNV abnormalities with PSR outcomes. Of all the diffusivity metrics, FA could be considered a novel objective quantitative indicator of treatment effects and a potential indicator of PSR effectiveness in TN patients.
Topics: Humans; Trigeminal Neuralgia; Male; Female; Rhizotomy; Middle Aged; Diffusion Tensor Imaging; Aged; Treatment Outcome; Adult; Trigeminal Nerve; Radiosurgery; Anisotropy; Prognosis
PubMed: 38649718
DOI: 10.1038/s41598-024-59828-4 -
Medicine Apr 2024Trigeminal herpes zoster, which comprises 10% to 20% of cases of herpes zoster, often leads to severe pain in the ophthalmic branches. Current treatments, including drug...
INTRODUCTION
Trigeminal herpes zoster, which comprises 10% to 20% of cases of herpes zoster, often leads to severe pain in the ophthalmic branches. Current treatments, including drug therapy and minimally invasive interventions, have limitations; accordingly, there is a need to explore alternative approaches. This study aimed to evaluate the efficacy and safety of computerized tomography (CT)-guided pulsed radiofrequency of the sphenopalatine ganglion in patients with intractable trigeminal herpetic pain.
PATIENT CONCERNS
Three patients with intractable trigeminal ophthalmic zoster neuralgia were studied. All patients complained of bursts of headache, which occurred at least 10 times a day, usually in the periorbital and frontal regions. Conventional treatments, including oral medications and radiofrequency therapy targeting the trigeminal-semilunar ganglion and supraorbital nerve, could not sufficiently provide relief.
DIAGNOSIS
Two patients were diagnosed with herpes zoster in the ocular branch of the trigeminal nerve with conjunctivitis, while one patient was diagnosed with postherpetic neuralgia in the ocular branch of the trigeminal nerve.
INTERVENTIONS
This study employed a novel approach that involved CT-guided radiofrequency regulation of the pterygopalatine fossa sphenopalatine ganglion.
OUTCOMES
In all three patients, pain relief was achieved within 1 to 3 days after treatment. During the follow-up, one patient had pain recurrence; however, its severity was ≈ 40% lower than the pretreatment pain severity. The second patient had sustained and effective pain relief. However, the pain of the third patient worsened again after 2 months. The average follow-up duration was 3 months. None of the enrolled patients showed treatment-related adverse reactions or complications.
CONCLUSION
Our findings indicated that CT-guided radiofrequency regulation of the pterygopalatine fossa sphenopalatine ganglion was a safe and effective intervention for pain in patients with trigeminal ophthalmic zoster neuralgia, suggesting that it may be a therapeutic option if other treatments fail.
Topics: Humans; Herpes Zoster Ophthalmicus; Pulsed Radiofrequency Treatment; Neuralgia; Neuralgia, Postherpetic; Trigeminal Neuralgia; Herpes Zoster; Pain, Intractable; Treatment Outcome
PubMed: 38640323
DOI: 10.1097/MD.0000000000037884 -
World Journal of Virology Mar 2024The aim of our minireview is to provide a brief overview of the diagnosis, clinical aspects, treatment options, management, and current literature available regarding... (Review)
Review
The aim of our minireview is to provide a brief overview of the diagnosis, clinical aspects, treatment options, management, and current literature available regarding herpes simplex keratitis (HSK). This type of corneal viral infection is caused by the herpes simplex virus (HSV), which can affect several tissues, including the cornea. One significant aspect of HSK is its potential to cause recurrent episodes of inflammation and damage to the cornea. After the initial infection, the HSV can establish a latent infection in the trigeminal ganglion, a nerve cluster near the eye. The virus may remain dormant for extended periods. Periodic reactivation of the virus can occur, leading to recurrent episodes of HSK. Factors triggering reactivation include stress, illness, immunosuppression, or trauma. Recurrent episodes can manifest in different clinical patterns, ranging from mild epithelial involvement to more severe stromal or endothelial disease. The severity and frequency of recurrences vary among individuals. Severe cases of HSK, especially those involving the stroma and leading to scarring, can result in vision impairment or even blindness in extreme cases. The cornea's clarity is crucial for good vision, and scarring can compromise this, potentially leading to visual impairment. The management of HSK involves not only treating acute episodes but also implementing long-term strategies to prevent recurrences and attempt repairs of corneal nerve endings neurotization. Antiviral medications, such as oral Acyclovir or topical Ganciclovir, may be prescribed for prophylaxis. The immune response to the virus can contribute to corneal damage. Inflammation, caused by the body's attempt to control the infection, may inadvertently harm the corneal tissues. Clinicians should be informed about triggers and advised on measures to minimize the risk of reactivation. In summary, the recurrent nature of HSK underscores the importance of both acute and long-term management strategies to preserve corneal health and maintain optimal visual function.
PubMed: 38616855
DOI: 10.5501/wjv.v13.i1.89934 -
Zhong Nan Da Xue Xue Bao. Yi Xue Ban =... Jan 2024Trigeminal neuralgia is a manifestation of orofacial neuropathic pain disorder, always deemed to be an insurmountable peak in the field of pain research and treatment....
Trigeminal neuralgia is a manifestation of orofacial neuropathic pain disorder, always deemed to be an insurmountable peak in the field of pain research and treatment. The pain is recurrent, abrupt in onset and termination similar to an electric shock or described as shooting. A poor quality of life has been attributed to trigeminal neuralgia, as the paroxysms of pain may be triggered by innocuous stimuli on the face or inside the oral cavity, such as talking, washing face, chewing and brushing teeth in daily life. The pathogenesis of trigeminal neuralgia has not been fully elucidated, although the microvascular compression in the trigeminal root entry zone is generally considered to be involved in the emergence and progression of the pain disorder. In addition, orofacial neuropathic pain restricted to one or more divisions of the trigeminal nerve might be secondary to peripheral nerve injury. Based on current hypotheses regarding the potential causes, a variety of animal models have been designed to simulate the pathogenesis of trigeminal neuralgia, including models of compression applied to the trigeminal nerve root or trigeminal ganglion, chronic peripheral nerve injury, peripheral inflammatory pain and center-induced pain. However, it has not yet been possible to determine which model can be perfectly employed to explain the mechanisms. The selection of appropriate animal models is of great significance for the study of trigeminal neuralgia. Therefore, it is necessary to discuss the characteristics of the animal models in terms of animal strains, materials, operation methods and behavior observation, in order to gain insight into the research progress in animal models of trigeminal neuralgia. In the future, animal models that closely resemble the features of human trigeminal neuralgia pathogenesis need to be developed, with the aim of making valuable contributions to the relevant basic and translational medical research.
Topics: Animals; Humans; Trigeminal Neuralgia; Quality of Life; Mastication; Models, Animal; Peripheral Nerve Injuries; Neuralgia
PubMed: 38615165
DOI: 10.11817/j.issn.1672-7347.2024.230279 -
Zhong Nan Da Xue Xue Bao. Yi Xue Ban =... Jan 2024Trigeminal neuralgia (TN) is a common neuropathic pain. Voltage-gated potassium channel (Kv) has been confirmed to be involved in the occurrence and development of TN,...
OBJECTIVES
Trigeminal neuralgia (TN) is a common neuropathic pain. Voltage-gated potassium channel (Kv) has been confirmed to be involved in the occurrence and development of TN, but the specific mechanism is still unclear. MicroRNA may be involved in neuropathic pain by regulating the expression of Kv channels and neuronal excitability in trigeminal ganglion (TG). This study aims to explore the relationship between Kv1.1 and in TG with a TN model, evaluate whether has a regulatory effect on Kv1.1, and to provide a new target and experimental basis for the treatment of TN.
METHODS
A total of 48 SD rats were randomly divided into 6 groups: 1) a sham group (=12), the rats were only sutured at the surgical incision without nerve ligation; 2) a sham+agomir NC group (=6), the sham rats were microinjected with agomir NC through stereotactic brain injection in the surgical side of TG; 3) a sham+ agomir group (=6), the sham rats were microinjected with agomir via stereotactic brain injection in the surgical side of TG; 4) a TN group (=12), a TN rat model was constructed using the chronic constriction injury of the distal infraorbital nerve (dIoN-CCI) method with chromium intestinal thread; 5) a TN+antagonist NC group (=6), TN rats were microinjected with antagonist NC through stereotactic brain injection method in the surgical side of TG; 6) a TN+ antagonist group (=6), TN rats were microinjected with antagonist through stereotactic brain injection in the surgical side of TG. The change of mechanical pain threshold in rats of each group after surgery was detected. The expressions of Kv1.1 and in the operative TG of rats were detected by Western blotting and real-time reverse transcription polymerase chain reaction. Dual luciferase reporter genes were used to determine whether there was a target relationship between Kv1.1 and and whether directly affected the 3'-UTR terminal of . The effect of brain stereotaxic injection was evaluated by immunofluorescence assay, and then the analogue of (agomir) and agomir NC were injected into the TG of rats in the sham group by brain stereotaxic apparatus to overexpress . The inhibitor (antagomir) and antagomir NC were injected into TG of rats in the TN group to inhibit the expression of . The behavioral changes of rats before and after administration were observed, and the expression changes of and Kv1.1 in TG of rats after intervention were detected.
RESULTS
Compared with the baseline pain threshold, the facial mechanical pain threshold of rats in the TN group was significantly decreased from the 5th to 15th day after the surgery (<0.05), and the facial mechanical pain threshold of rats in the sham group was stable at the normal level, which proved that the dIoN-CCI model was successfully constructed. Compared with the sham group, the expression of mRNA and protein in TG of the TN group was down-regulated (both <0.05), and the expression of was up-regulated (<0.05). The results of dual luciferase report showed that the luciferase activity of rno- mimics and WT transfected with 6 nmol/L or 20 nmol/L were significantly decreased compared with those transfected with mimic NC and wild-type WT, respectively (<0.001). Compared with low dose rno- mimics (6 nmol/L) co-transfection group, the relative activity of luciferase in the high dose rno- mimics (20 nmol/L) cotransfection group was significantly decreased (<0.001). The results of immunofluorescence showed that drugs were accurately injected into TG through stereotaxic brain. After the expression of in the TN group, the mechanical pain threshold and the expression of mRNA and protein in TG were increased. After overexpression of in the sham group, the mechanical pain threshold and the expression of mRNA and protein in TG were decreased.
CONCLUSIONS
Both Kv1.1 and are involved in TN and can regulate Kv1.1 expression by binding to the 3'-UTR of KCNA1.
Topics: Animals; Rats; Antagomirs; Down-Regulation; Luciferases; MicroRNAs; Neuralgia; Rats, Sprague-Dawley; RNA, Messenger; Trigeminal Neuralgia; Kv1.1 Potassium Channel
PubMed: 38615163
DOI: 10.11817/j.issn.1672-7347.2024.230273