Activation of CXCL10/CXCR3 Signaling Attenuates Morphine Analgesia: Involvement of Gi Protein

Ye, Dawei; Bu, Huilian; Guo, Genhua; Shu, Bin; Wang, Wei; Guan, Xue-Hai; Yang, Hui; Tian, Xiaojing; Xiang, Hong‐Bing; Gao, Feng

doi:10.1007/s12031-013-0223-1

Cited by 48 publications

(33 citation statements)

References 31 publications

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“…Interestingly, our previous study verified that the chemokines CXCL10 and its receptor CXCR3 were markedly elevated in CIBP (Guan et al, 2015;Ye et al, 2014;Zhou et al, 2015). Moreover, recent studies also demonstrated that CXCR3 could express on the surface of CD8 + T cells (Laragione et al, 2011;Tokuriki et al, 2002).…”

Section: Discussionsupporting

confidence: 55%

MHC-I promotes apoptosis of GABAergic interneurons in the spinal dorsal horn and contributes to cancer induced bone pain

Shi

Zhou

et al. 2016

Experimental Neurology

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Cancer induced bone pain (CIBP) remains one of the most intractable clinical problems due to poor understanding of its underlying mechanisms. Recent studies demonstrate the decline of inhibitory interneurons, especially GABAergic interneurons in the spinal cord, can evoke generation of chronic pain. It has also been reported that neuronal MHC-I expression renders neurons vulnerable to cytotoxic CD8 T cells and finally lead to neurons apoptosis in a variety neurological disorders. However, whether MHC-I could induce the apoptosis of GABAergic interneurons in spinal cord and contribute to the development of CIBP remains unknown. In this study, we investigated roles of MHC-I and underlying mechanisms in CIBP on a rat model. Our results showed that increased MHC-I expression on GABAergic interneurons could deplete GABAergic interneurons by inducing their apoptosis in the spinal dorsal horn of tumor-bearing rats. Pretreatment of MHC-I RNAi-lentivirus could prevent the apoptosis of GABAergic interneurons and therefore alleviated mechanical allodynia induced by tumor cells intratibial injection. Additionally, we also found that CD8 T cells were colocalized with MHC-I and GABAergic neurons and presented a significant and persistent increase in the spinal cord of tumor-bearing rats. Taken together, these findings indicated that MHC-I could evoke CIBP by promoting apoptosis of GABAergic interneurons in the dorsal horn, and this apoptosis was closely related to local CD8 T cells.

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Section: Discussionsupporting

confidence: 55%

MHC-I promotes apoptosis of GABAergic interneurons in the spinal dorsal horn and contributes to cancer induced bone pain

Shi

Zhou

et al. 2016

Experimental Neurology

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“…Previous study has reported that CXCL10 was upregulated in nervous system with neuroinflammatory pain (Müller et al, 2010). Recently, our studies have shown that single morphine administration promoted CXCL10 expression in spinal neurons, while blocking the function of CXCL10 could enhance the effect of morphine analgesia in cancer pain animal (Ye et al, 2014;Bu et al, 2014). In addition, CXCR3 was co-localized with neuron, astrocyte and microglia in bone cancer pain model (Guan et al, 2015), suggesting CXCL10/CXCR3-related neuron-microglia interaction may play a critical role in the formation of bone cancer pain and morphine analgesic effect.…”

Section: Introductionmentioning

confidence: 74%

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

et al. 2017

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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.

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“…The overexpression of CXCL10 due to activation of CXCR3 and G i protein results in an attenuation of opioid-induced analgesia. However, blocking CXCL10 spinal function enhanced the morphine antinociceptive properties in rats with cancer-induced bone pain (Ye et al 2014). Thus, increasing evidence points to cross-talk between opioid and chemokine receptors, which both belong to the G-protein coupling receptors (GPCRs) superfamily.…”

Section: Discussionmentioning

confidence: 99%

The RS504393 Influences the Level of Nociceptive Factors and Enhances Opioid Analgesic Potency in Neuropathic Rats

Kwiatkowski

Piotrowska

Rojewska

et al. 2017

J Neuroimmune Pharmacol

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Increasing evidence has indicated that activated glial cells releasing nociceptive factors, such as interleukins and chemokines, are of key importance for neuropathic pain. Significant changes in the production of nociceptive factors are associated with the low effectiveness of opioids in neuropathic pain. Recently, it has been suggested that CCL2/CCR2 signaling is important for nociception. Here, we studied the time course changes in the mRNA/protein level of CD40/Iba-1, CCL2 and CCR2 in the spinal cord/dorsal root ganglia (DRG) in rats following chronic constriction injury (CCI) of the sciatic nerve. Moreover, we examined the influence of intrathecal preemptive and repeated (daily for 7 days) administration of RS504393, CCR2 antagonist, on pain-related behavior and the associated biochemical changes of some nociceptive factors as well as its influence on opioid effectiveness. We observed simultaneous upregulation of Iba-1, CCL2, CCR2 in the spinal cord on 7th day after CCI. Additionally, we demonstrated that repeated administration of RS504393 not only attenuated tactile/thermal hypersensitivity but also enhanced the analgesic properties of morphine and buprenorphine under neuropathy. Our results proof that repeated administration of RS504393 reduced the mRNA and/or protein levels of pronociceptive factors, such as IL-1beta, IL-18, IL-6 and inducible nitric oxide synthase (iNOS), and some of their receptors in the spinal cord and/or DRG. Furthermore, RS504393 elevated the spinal protein level of antinociceptive IL-1alpha and IL-18 binding protein. Our data provide new evidence that CCR2 is a promising target for diminishing neuropathic pain and enhancing the opioid analgesic effects.

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Activation of CXCL10/CXCR3 Signaling Attenuates Morphine Analgesia: Involvement of Gi Protein

Cited by 48 publications

References 31 publications

MHC-I promotes apoptosis of GABAergic interneurons in the spinal dorsal horn and contributes to cancer induced bone pain

MHC-I promotes apoptosis of GABAergic interneurons in the spinal dorsal horn and contributes to cancer induced bone pain

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

The RS504393 Influences the Level of Nociceptive Factors and Enhances Opioid Analgesic Potency in Neuropathic Rats

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