The core of maintaining neuropathic pain: Crosstalk between glial cells and neurons (neural cell crosstalk at spinal cord)

Zhang, Tianrui; Zhang, Mingqian; Cui, Shuang; Liang, Wulin; Jia, Zhanhong; Guo, Fengwei; Ou, Wen; Wu, Yonghong; Zhang, Shuofeng

doi:10.1002/brb3.2868

Cited by 21 publications

(6 citation statements)

References 195 publications

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“…Microglia and astrocyte activation lead to overregulation of chemokines and increased signalling between neurons and glial cells. Moreover, neurons can maintain glial cell activation through chemokines and related pathways [67]. Among the different mediators implicated in these interactions, a role is played by cytokines, like IL-1beta [68][69][70], whose expression in the present study was found to be increased in trigeminal areas of operated animals, along with other pro-inflammatory molecules.…”

Section: Discussionsupporting

confidence: 46%

URB937 Prevents the Development of Mechanical Allodynia in Male Rats with Trigeminal Neuralgia

Demartini,

Greco,

Zanaboni

et al. 2023

Pharmaceuticals

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Cannabinoids are proposed for alleviating neuropathic pain, but their use is limited by cannabimimetic side effects. The inhibition of the fatty acid amide hydrolase (FAAH), the degrading enzyme of the endocannabinoid anandamide, has received attention as an alternative to cannabinoids in the treatment of neuropathic pain. Here, we investigated the effect of URB937, a blood–brain barrier impermeant FAAH inhibitor, on experimentally induced mechanical allodynia in an animal model of trigeminal neuralgia. Male Sprague-Dawley rats were subjected to chronic constriction injury of the infraorbital nerve (IoN-CCI); operated animals were treated sub-chronically with URB937 (1 mg/kg, i.p.) or vehicle before or after trigeminal mechanical allodynia establishment. We also assayed mRNA expression levels of the pain neuropeptide calcitonin gene-related peptide (CGRP) and cytokines in the medulla, cervical spinal cord, and trigeminal ganglion ipsilateral to IoN-CCI using rt-PCR. URB937 treatment prevented the development of mechanical allodynia and IoN-CCI-induced changes in mRNA expression levels of CGRP and cytokines in the evaluated areas. When administered after allodynia development, URB937 prevented IoN-CCI-induced changes in CGRP and cytokine gene expression; this was not associated with a significant abrogation of the mechanical allodynia. These findings suggest that URB937 may counteract, but not reverse, the development of allodynia in trigeminal neuralgia. Further research is needed to elucidate the underlying mechanisms.

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Section: Discussionsupporting

confidence: 46%

URB937 Prevents the Development of Mechanical Allodynia in Male Rats with Trigeminal Neuralgia

Demartini,

Greco,

Zanaboni

et al. 2023

Pharmaceuticals

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“…Based on the strong effect of SAFit2 on pain-mediating chemokines in the lumbar DRGs and spinal cord, we investigated the effect of SAFit2 regarding spinal gliosis, since activated astrocytes and microglia are the predominant source of cytokines and chemokines in the spinal cord [ 30 , 31 ]. To assess this, we performed immunohistochemical stainings of dorsal horn samples to assess the activation of astrocytes and the number of microglia (Fig.…”

Section: Resultsmentioning

confidence: 99%

SAFit2 ameliorates paclitaxel-induced neuropathic pain by reducing spinal gliosis and elevating pro-resolving lipid mediators

Wedel

Hahnefeld

Schreiber

et al. 2023

J Neuroinflammation

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Background Chemotherapy-induced neuropathic pain (CIPN) describes a pathological pain state that occurs dose-dependently as a side effect and can limit or even impede an effective cancer therapy. Unfortunately, current treatment possibilities for CIPN are remarkably confined and mostly inadequate as CIPN therapeutics themselves consist of low effectiveness and may induce severe side effects, pointing out CIPN as pathological entity with an emerging need for novel treatment targets. Here, we investigated whether the novel and highly specific FKBP51 inhibitor SAFit2 reduces paclitaxel-induced neuropathic pain. Methods In this study, we used a well-established multiple low-dose paclitaxel model to investigate analgesic and anti-inflammatory properties of SAFit2. For this purpose, the behavior of the mice was recorded over 14 days and the mouse tissue was then analyzed using biochemical methods. Results Here, we show that SAFit2 is capable to reduce paclitaxel-induced mechanical hypersensitivity in mice. In addition, we detected that SAFit2 shifts lipid levels in nervous tissue toward an anti-inflammatory and pro-resolving lipid profile that counteracts peripheral sensitization after paclitaxel treatment. Furthermore, SAFit2 reduced the activation of astrocytes and microglia in the spinal cord as well as the levels of pain-mediating chemokines. Its treatment also increased anti-inflammatory cytokines levels in neuronal tissues, ultimately leading to a resolution of neuroinflammation. Conclusions In summary, SAFit2 shows antihyperalgesic properties as it ameliorates paclitaxel-induced neuropathic pain by reducing peripheral sensitization and resolving neuroinflammation. Therefore, we consider SAFit2 as a potential novel drug candidate for the treatment of paclitaxel-induced neuropathic pain.

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“…CNS involvement can account for bilateral neuropathy symptoms, which may be due to DRGn hyperactivity-induced hyperexcitability of wide dynamic range neurons and activation of commissural neurons of the spinal cord ( 66 ), or, also supposedly, due to systemic neuroinflammation-mediated mechanisms ( 42 , 66 ). Extraterritorial hypersensitivity may be shaped by neuron crosstalk not only in the CNS ( 112 , 113 ) but also in the DRG ( 83 ). Notably, allodynia involves functional interplay between nociceptive and non-nociceptive pathways ( 2 , 16 ).…”

Section: Pre-hypothetical Reasoning: Ectopic Nociceptive Sensitizatio...mentioning

confidence: 99%

Chronic pain and local pain in usually painless conditions including neuroma may be due to compressive proximal neural lesion

Macionis¹

2023

Front. Pain Res.

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It has been unexplained why chronic pain does not invariably accompany chronic pain-prone disorders. This question-driven, hypothesis-based article suggests that the reason may be varying occurrence of concomitant peripheral compressive proximal neural lesion (cPNL), e.g., radiculopathy and entrapment plexopathies. Transition of acute to chronic pain may involve development or aggravation of cPNL. Nociceptive hypersensitivity induced and/or maintained by cPNL may be responsible for all types of general chronic pain as well as for pain in isolated tissue conditions that are usually painless, e.g., neuroma, scar, and Dupuytren's fibromatosis. Compressive PNL induces focal neuroinflammation, which can maintain dorsal root ganglion neuron (DRGn) hyperexcitability (i.e., peripheral sensitization) and thus fuel central sensitization (i.e., hyperexcitability of central nociceptive pathways) and a vicious cycle of chronic pain. DRGn hyperexcitability and cPNL may reciprocally maintain each other, because cPNL can result from reflexive myospasm-induced myofascial tension, muscle weakness, and consequent muscle imbalance- and/or pain-provoked compensatory overuse. Because of pain and motor fiber damage, cPNL can worsen the causative musculoskeletal dysfunction, which further accounts for the reciprocity between the latter two factors. Sensitization increases nerve vulnerability and thus catalyzes this cycle. Because of these mechanisms and relatively greater number of neurons involved, cPNL is more likely to maintain DRGn hyperexcitability in comparison to distal neural and non-neural lesions. Compressive PNL is associated with restricted neural mobility. Intermittent (dynamic) nature of cPNL may be essential in chronic pain, because healed (i.e., fibrotic) lesions are physiologically silent and, consequently, cannot provide nociceptive input. Not all patients may be equally susceptible to develop cPNL, because occurrence of cPNL may vary as vary patients' predisposition to musculoskeletal impairment. Sensitization is accompanied by pressure pain threshold decrease and consequent mechanical allodynia and hyperalgesia, which can cause unusual local pain via natural pressure exerted by space occupying lesions or by their examination. Worsening of local pain is similarly explainable. Neuroma pain may be due to cPNL-induced axonal mechanical sensitivity and hypersensitivity of the nociceptive nervi nervorum of the nerve trunk and its stump. Intermittence and symptomatic complexity of cPNL may be the cause of frequent misdiagnosis of chronic pain.

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The core of maintaining neuropathic pain: Crosstalk between glial cells and neurons (neural cell crosstalk at spinal cord)

Cited by 21 publications

References 195 publications

URB937 Prevents the Development of Mechanical Allodynia in Male Rats with Trigeminal Neuralgia

URB937 Prevents the Development of Mechanical Allodynia in Male Rats with Trigeminal Neuralgia

SAFit2 ameliorates paclitaxel-induced neuropathic pain by reducing spinal gliosis and elevating pro-resolving lipid mediators

Chronic pain and local pain in usually painless conditions including neuroma may be due to compressive proximal neural lesion

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