Blockade of neuronal dopamine D2 receptor attenuates morphine tolerance in mice spinal cord.

Wen-Ling Dai,Bo-Yang Yu,Feng Xiong,Ji-Hua Liu,Bing Yan,Zheng-Yu Cao,Wen-Tao Liu

doi:10.1038/srep38746

Abstract

Tolerance induced by morphine remains a major unresolved problem and significantly limits its clinical use. Recent evidences have indicated that dopamine D2 receptor (D2DR) is likely to be involved in morphine-induced antinociceptive tolerance. However, its exact effect and molecular mechanism remain unknown. In this study we examined the effect of D2DR on morphine antinociceptive tolerance in mice spinal cord. Chronic morphine treatment significantly increased levels of D2DR in mice spinal dorsal horn. And the immunoreactivity of D2DR was newly expressed in neurons rather than astrocytes or microglia both in vivo and in vitro. Blockade of D2DR with its antagonist (sulpiride and L-741,626, i.t.) attenuated morphine antinociceptive tolerance without affecting basal pain perception. Sulpiride (i.t.) also down-regulated the expression of phosphorylation of NR1, PKC, MAPKs and suppressed the activation of astrocytes and microglia induced by chronic morphine administration. Particularly, D2DR was found to interact with μ opioid receptor (MOR) in neurons, and chronic morphine treatment enhanced the MOR/D2DR interactions. Sulpiride (i.t.) could disrupt the MOR/D2DR interactions and attenuate morphine tolerance, indicating that neuronal D2DR in the spinal cord may be involved in morphine tolerance possibly by interacting with MOR. These results may present new opportunities for the treatment and management of morphine-induced antinociceptive tolerance which often observed in clinic.

Highlights

Morphine is a highly efficacious agent against chronic severe pain
Confocal images showed that D2DR immunoreactivity was co-localized with the mature neuronal marker NeuN, but not the astrocytic marker GFAP or the microglial marker IBA1 (Fig. 2)
We have demonstrated for the first time that chronic morphine administration significantly increase neuronal D2DR protein level in mice spinal dorsal horn

Summary

Introduction

Morphine is a highly efficacious agent against chronic severe pain. repeated morphine administration leads to antinociceptive tolerance which discontinues morphine therapy for chronic pain. In MOR-1 knockout mice, the analgesia and tolerance of morphine are absent[1,2]. Chronic morphine treatment can significantly increase the release of different neurotransmitters such as glutamate (Glu), which binds to the NMDA receptor to enhance the excitatory synaptic transmission[5,6]. It activates the astrocytes and microglia[7,8,9], leading to the release of the pro-inflammatory cytokines such as tumor necrosis factor-α(TNFα)and interleukin-1β(IL-1β)[10,11,12] to promote the morphine tolerance. Our results indicated that chronic morphine treatment increased the neuronal D2DR expression www.nature.com/scientificreports/

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Results

Conclusion