Neuroligins facilitate the development of bone cancer pain via regulating synaptic transmission: an experimental study
As neuroliginas facilitam o desenvolvimento da dor do câncer ósseo através da regulação da transmissão sináptica: um estudo experimental
Xianqiao Xie, Yang Li, Shanchun Su, Xiaohui Li, Xueqin Xu, Yan Gao, Minjing Peng, Changbin Ke
Abstract
Background
The underlying mechanism of chronic pain involves the plasticity in synaptic receptors and neurotransmitters. This study aimed to investigate potential roles of Neuroligins (NLs) within the spinal dorsal horn of rats in a newly established Bone Cancer Pain (BCP) model. The objective was to explore the mechanism of neuroligin involved in the occurrence and development of bone cancer pain.
Methods
Using our rat BCP model, we assessed pain hypersensitivity over time. Quantitative real-time polymerase chain reaction and Western blot analysis were performed to investigate NL expression, and NLs were overexpressed in the rat spinal cord using lentiviral vectors. Immunofluorescence staining and whole-cell patch-clamp recordings were deployed to investigate the role of NLs in the development of BCP.
Results
We observed reduced expression levels of NL1 and NL2, but not of NL3, within the rat spinal cord, which were found to be associated with and essential for the development of BCP in our model. Accordingly, NL1 or NL2 overexpression in the spinal cord alleviated mechanical hypersensitivity of rats. Electrophysiological experiments indicated that NL1 and NL2 are involved in BCP via regulating γ-aminobutyric acid-ergic interneuronal synapses and the activity of glutamatergic interneuronal synapses, respectively.
Conclusions
Our observations unravel the role of NLs in cancer-related chronic pain and further suggest that inhibitory mechanisms are central features of BCP in the spinal dorsal horn. These results provide a new perspective and basis for subsequent studies elucidating the onset and progression of BCP.
Keywords
Resumo
Introdução
O mecanismo subjacente da dor crônica envolve a plasticidade dos receptores sinápticos e neurotransmissores. Este estudo teve como objetivo investigar os papéis potenciais das neuroliginas (NLs) no corno espinhal dorsal de ratos em um modelo recém-estabelecido de dor por câncer ósseo (BCP). O objetivo foi explorar o mecanismo da neuroligina envolvido na ocorrência e desenvolvimento da dor do câncer ósseo.
Métodos
Usando nosso modelo BCP de rato, avaliamos a hipersensibilidade à dor ao longo do tempo. A reação em cadeia da polimerase quantitativa em tempo real e a análise de Western blot foram realizadas para investigar a expressão de NL, e os NLs foram superexpressos na medula espinhal de ratos usando vetores lentivirais. A coloração por imunofluorescência e os registros de patch-clamp de células inteiras foram implantados para investigar o papel dos NLs no desenvolvimento do BCP.
Resultados
Observamos níveis reduzidos de expressão de NL1 e NL2, mas não de NL3, na medula espinhal de ratos, que foram associados e essenciais para o desenvolvimento de BCP em nosso modelo. Consequentemente, a superexpressão de NL1 ou NL2 na medula espinhal aliviou a hipersensibilidade mecânica de ratos. Experimentos eletrofisiológicos indicaram que NL1 e NL2 estão envolvidos no BCP através da regulação das sinapses interneuronais alérgicas ao ácido γ-aminobutírico e da atividade das sinapses interneuronais glutamatérgicas, respectivamente.
Conclusão
Nossas observações desvendam o papel dos NLs na dor crônica relacionada ao câncer e sugerem ainda que os mecanismos inibitórios são características centrais do BCP no corno dorsal da coluna vertebral. Estes resultados fornecem uma nova perspectiva e base para estudos subsequentes que elucidam o início e a progressão do BCP.
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References
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Submitted date:
09/20/2022
Accepted date:
02/13/2023
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