Potential role of CXCL10/CXCR3 signaling in the development of morphine tolerance in periaqueductal gray

Tolerance to morphine antinociception hinders its long-term use in clinical practice. Interaction between neuron and microglia has been proved to play critical role in the mechanism of morphine tolerance, while CXCL10/CXCR3 signaling has been implicated in neuron-glia signaling and morphine analgesia. This study aims to investigate whether CXCL10/CXCR3 signaling in periaqueductal gray (PAG) contributes to the development of morphine tolerance by modulating neuron-microglia interaction. The results showed that the expressions of CXCR3 and CXCL10 were gradually increased in parallel with repeated morphine administration and activation of microglia. CXCR3 was co-localized with neuronal marker NeuN, while CXCL10 was derived from microglia. Microglia inhibitor minocycline significantly attenuated the expression of CXCL10, besides, both minocycline and CXCR3 inhibitor alleviated the development of morphine tolerance. Taken together, our study provided the evidence that CXCL10/CXCR3 signaling in PAG is involved in the development of morphine analgesic tolerance via neuron-microglia interaction.