Dataset Information

Blockade of spinal dopamine D1/D2 receptor suppresses activation of NMDA receptor through G?q and Src kinase to attenuate chronic bone cancer pain.

ABSTRACT:

Introduction

Spinal N-methyl-D-aspartate receptor (NMDAR) is vital in chronic pain, while NMDAR antagonists have severe side effects. NMDAR has been reported to be controlled by G protein coupled receptors (GPCRs), which might present new therapeutic targets to attenuate chronic pain. Dopamine receptors which belong to GPCRs have been reported could modulate the NMDA-mediated currents, while their exact effects on NMDAR in chronic bone cancer pain have not been elucidated.

Objectives

This study was aim to explore the effects and mechanisms of dopamine D1 receptor (D1DR) and D2 receptor (D2DR) on NMDAR in chronic bone cancer pain.

Methods

A model for bone cancer pain was established using intra-tibia bone cavity tumor cell implantation (TCI) of Walker 256 in rats. The nociception was assessed by Von Frey assay. A range of techniques including the fluorescent imaging plate reader, western blotting, and immunofluorescence were used to detect cell signaling pathways. Primary cultures of spinal neurons were used for in vitro evaluation.

Results

Both D1DR and D2DR antagonists decreased NMDA-induced upregulation of Ca²⁺ oscillations in primary culture spinal neurons. Additionally, D1DR/D2DR antagonists inhibited spinal Calcitonin Gene-Related Peptide (CGRP) and c-Fos expression and alleviated bone cancer pain induced by TCI which could both be reversed by NMDA. And D1DR/D2DR antagonists decreased p-NR1, p-NR2B, and G?q protein, p-Src expression. Both G?q protein and Src inhibitors attenuated TCI-induced bone cancer pain, which also be reversed by NMDA. The G?q protein inhibitor decreased p-Src expression. In addition, D1DR/D2DR antagonists, Src, and G?q inhibitors inhibited spinal mitogen-activated protein kinase (MAPK) expression in TCI rats, which could be reversed by NMDA.

Conclusions

Spinal D1DR/D2DR inhibition eliminated NMDAR-mediated spinal neuron activation through Src kinase in a G?q-protein-dependent manner to attenuate TCI-induced bone cancer pain, which might present a new therapeutic strategy for bone cancer pain.

SUBMITTER: Dai WL

PROVIDER: S-EPMC7753228 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Publications

Blockade of spinal dopamine D1/D2 receptor suppresses activation of NMDA receptor through Gαq and Src kinase to attenuate chronic bone cancer pain.

Dai Wen-Ling WL Bao Yi-Ni YN Fan Ji-Fa JF Ma Bin B Li Shan-Shan SS Zhao Wan-Li WL Yu Bo-Yang BY Liu Ji-Hua JH

Journal of advanced research 20200813

<h4>Introduction</h4>Spinal N-methyl-D-aspartate receptor (NMDAR) is vital in chronic pain, while NMDAR antagonists have severe side effects. NMDAR has been reported to be controlled by G protein coupled receptors (GPCRs), which might present new therapeutic targets to attenuate chronic pain. Dopamine receptors which belong to GPCRs have been reported could modulate the NMDA-mediated currents, while their exact effects on NMDAR in chronic bone cancer pain have not been elucidated.<h4>Objectives< ...[more]

PMID: 33364051

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