Sodium Channel Blockers Modulate Abnormal Activity of Regenerating Nociceptive Corneal Nerves After Surgical Lesion

Luna, Carolina; Mizerska, Kamila; Quirce, Susana; Belmonte, Carlos; Gallar, Juana; Acosta, M. Carmen; Meseguer, Víctor

doi:10.1167/iovs.62.1.2

Cited by 15 publications

(17 citation statements)

References 73 publications

(87 reference statements)

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“…[33][34][35][36] Hence, there is a major unmet need to develop specific sodium channel blockers to treat inflammation and chronic neuropathic pain. [37][38][39][40][41][42] Further, this has led to increased prescription of opioid analgesics for chronic neuropathic pain paving the way to opioid abuse and addiction according to Centers for Disease Control (CDC) and American College of Physicians. [43][44][45] Therefore, it is imperative to identify non-opioid drug candidates that can alleviate inflammation and chronic neuropathic pain.…”

Section: Resultsmentioning

confidence: 99%

“…Several studies have linked voltage-gated sodium channels (VGSCs) as contributing to pain syndromes through enhanced electrical currents and increased sodium channel density at sites of injury. [37][38][39][40] VGSCs would be ideal therapeutic target for neuropathic and chronic pain. [36,37,39] Further affinity studies are required to test if C2 and C3 can effectively block VGSCs in human cells.…”

Section: Discussionmentioning

confidence: 99%

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Discovery of Quinoline‐Derived Trifluoromethyl Alcohols as Antiepileptic and Analgesic Agents That Block Sodium Channels

et al. 2021

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The discovery of novel analgesic agents with high potency, low toxicity and low addictive properties remain a priority. This study aims to identify the analgesic potential of quinoline derived α-trifluoromethylated alcohols (QTA) and their mechanism of action. We synthesized and characterized several compounds of QTAs and screened them for antiepileptic and analgesic activity using zebrafish larvae in high thorough-put behavior analyses system. Toxicity and behavioral screening of 9 compounds (C1-C9) identified four candidates (C2, C3, C7 and C9) with antiepileptic properties that induces specific and reversible reduction in photomotor activity. Importantly, compounds C2 and C3 relieved the thermal pain response in zebrafish larvae indicating analgesic property. Further, using novel in vivo CoroNa green assay, we show that compounds C2 and C3 block sodium channels and reduce inflammatory sodium signals released by peripheral nerve and tissue damage. Thus, we have identified novel QTA compounds with antiepileptic and analgesic properties which could alleviate neuropathic pain.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Discovery of Quinoline‐Derived Trifluoromethyl Alcohols as Antiepileptic and Analgesic Agents That Block Sodium Channels

et al. 2021

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“…After inflammation or lesion, corneal sensory nerve activity is altered. Like in other tissues, corneal nociceptors (specially polymodal nociceptors) are sensitized [ 64 , 69 , 74 , 75 , 76 , 77 , 78 , 79 ], a functional state characterized by an increase in spontaneous activity, a reduction in the response threshold, and an increased response to stimulation. Sensitization constitutes the basis of spontaneous pain and hyperalgesia experienced during inflammation.…”

Section: The Corneamentioning

confidence: 99%

An Experimental Model of Neuro–Immune Interactions in the Eye: Corneal Sensory Nerves and Resident Dendritic Cells

Frutos-Rincón

Gomez-Sanchez

Íñigo-Portugués

et al. 2022

IJMS

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The cornea is an avascular connective tissue that is crucial, not only as the primary barrier of the eye but also as a proper transparent refractive structure. Corneal transparency is necessary for vision and is the result of several factors, including its highly organized structure, the physiology of its few cellular components, the lack of myelinated nerves (although it is extremely innervated), the tightly controlled hydration state, and the absence of blood and lymphatic vessels in healthy conditions, among others. The avascular, immune-privileged tissue of the cornea is an ideal model to study the interactions between its well-characterized and dense sensory nerves (easily accessible for both focal electrophysiological recording and morphological studies) and the low number of resident immune cell types, distinguished from those cells migrating from blood vessels. This paper presents an overview of the corneal structure and innervation, the resident dendritic cell (DC) subpopulations present in the cornea, their distribution in relation to corneal nerves, and their role in ocular inflammatory diseases. A mouse model in which sensory axons are constitutively labeled with tdTomato and DCs with green fluorescent protein (GFP) allows further analysis of the neuro-immune crosstalk under inflammatory and steady-state conditions of the eye.

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“…Voltage-dependent sodium channels (Na v ) are actively involved in corneal nociceptor sensitization: perfusion with amitriptyline (a Na v channel blocker) was less effective in teardeficient mice, suggesting the occurrence of changes in the expression of these channels induced by ocular dryness (Masuoka et al, 2018). In guinea pig excised eyes, previously subjected to a corneal surgical lesion, AP discharges of PNs were increased in response to chemical corneal stimulation (CO 2 application) (Luna et al, 2021). Similarly, removal of the main Bereiter and Bereiter (1996), Meng and Bereiter (1996), Martinez and Belmonte (1996), Meng et al (1997), Meng et al (1998), Hirata et al (2000), Hirata et al (2004) lachrymal gland in guinea pigs enhanced the ongoing AP firing and the responses to cooling of corneal CRs.…”

Section: Molecular Mechanisms Of Peripheral Pain Sensitizationmentioning

confidence: 99%

“…axons surrounded by connective tissue and immune cells) and accumulation of ion channels in the neural stumps ( Lisney and Devor, 1987 ; Devor et al, 1993 ). This can lead to an aberrant function of the peripheral nerve endings, generating spontaneous impulse bursts in absence of stimulation (ectopic activity) and/or paroxysmal firing in response to mild mechanical and chemical stimuli ( Rivera et al, 2000 ; Luna et al, 2021 ).…”

Section: Peripheral Mechanisms Mediating Ocular Painmentioning

confidence: 99%

Mechanisms of Peripheral and Central Pain Sensitization: Focus on Ocular Pain

2021

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Persistent ocular pain caused by corneal inflammation and/or nerve injury is accompanied by significant alterations along the pain axis. Both primary sensory neurons in the trigeminal nerves and secondary neurons in the spinal trigeminal nucleus are subjected to profound morphological and functional changes, leading to peripheral and central pain sensitization. Several studies using animal models of inflammatory and neuropathic ocular pain have provided insight about the mechanisms involved in these maladaptive changes. Recently, the advent of new techniques such as optogenetics or genetic neuronal labelling has allowed the investigation of identified circuits involved in nociception, both at the spinal and trigeminal level. In this review, we will describe some of the mechanisms that contribute to the perception of ocular pain at the periphery and at the spinal trigeminal nucleus. Recent advances in the discovery of molecular and cellular mechanisms contributing to peripheral and central pain sensitization of the trigeminal pathways will be also presented.

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Sodium Channel Blockers Modulate Abnormal Activity of Regenerating Nociceptive Corneal Nerves After Surgical Lesion

Cited by 15 publications

References 73 publications

Discovery of Quinoline‐Derived Trifluoromethyl Alcohols as Antiepileptic and Analgesic Agents That Block Sodium Channels

Discovery of Quinoline‐Derived Trifluoromethyl Alcohols as Antiepileptic and Analgesic Agents That Block Sodium Channels

An Experimental Model of Neuro–Immune Interactions in the Eye: Corneal Sensory Nerves and Resident Dendritic Cells

Mechanisms of Peripheral and Central Pain Sensitization: Focus on Ocular Pain

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