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postgraduate thesis: The role of CXCL12/CXCR4 axis in central mechanisms of pathological pain

TitleThe role of CXCL12/CXCR4 axis in central mechanisms of pathological pain
Authors
Issue Date2015
PublisherThe University of Hong Kong (Pokfulam, Hong Kong)
Citation
Luo, X. [羅昕]. (2015). The role of CXCL12/CXCR4 axis in central mechanisms of pathological pain. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b5736685
AbstractPathological pain is a disease induced by abnormal pain perception under various pathological conditions, and the central mechanisms contribute to the chronification of pain symptom. Axis consisting of chemokine C-X-C motif ligand 12 (CXCL12) and its receptor chemokine C-X-C motif receptor 4 (CXCR4) is considered an emerging neuromodulator. However, the function of CXCL12/CXCR4 axis in the central mechanisms of pathological pain, especially neuropathic pain, and the mechanisms underlying its roles were still under investigation. The present study firstly explored the role of central CXCL12/CXCR4 axis in the pathophysiology of neuropathic pain. In this study, the pharmacologic effects of a single intrathecal injection of a CXCR4 antagonist (AMD3100) were assessed in a mouse model of peripheral neuropathic pain (PNP) developed using partial sciatic nerve ligation (pSNL). The results showed that, in the pSNL model, AMD3100 attenuated the development and maintenance of mechanical allodynia in a dose-dependent way without impairing motor function. It was further showed that AMD3100 downregulated the spinal levels of p65, phosphorylated-JNK1and phosphorylated-p38 in pSNL-injured mice on post-operative day (POD) 7as determined by western blotting. It was also found that the mRNA level of substance P was decreased while the mRNA levels of adrenomedullin and intercellular adhesion molecule was increased in the ipsilateral spinal cord of pSNL-injured mice with the intrathecal injection of AMD3100on POD 7. Even CXCL12/CXCR4 axis was shown to contribute to various pathological pain conditions, especially neuropathic pain, although the common mechanisms for its rolein the central pain perception were not known. The second study unveiled that the glial-glial crosstalk might account for the involvement of CXCL12/CXCR4 axis in the pathogenesis of neuropathic pain. In this study, two mouse models of neuropathic pain, pSNL model and chronic post-ischemia pain (CPIP) model, were used. It was found that CXCL12was mainly expressed in astrocyte, whereas CXCR4 in both astrocyte and microglia in spinal cord dorsal horn of naïve mice. In the pSNL or CPIP model, the spinal level of CXCL12 was upregulated in astrocyte on POD3. The combined intrathecal injection of CXCL12 with minocycline (microglia inhibitor) or AMD3100, but not fluorocitrate (astrocyte inhibitor), attenuated CXCL12-induced mechanical allodynia. Furthermore, AMD3465 or AMD3100 (CXCR4 antagonists), being administered daily at1 hour before surgery and up to POD 3, delayed the development of mechanical allodynia in the two animal pain models. Moreover, intrathecal AMD3100 decreased mRNA levels of pro-inflammatory cytokines (IL-6,IL-1βand TNFα) but did not affect those of CGRP, prodynorphin or Substance P in two pain models on POD 3. In conclusion, the studies related to my PhD thesis demonstrates that central CXCL12/CXCR4 axis contributes to the pathophysiology of neuropathic pain via glial mechanisms and might offer insights for further research on the roles and mechanisms of CXCL12/CXCR4 axis in the pain perception.
DegreeDoctor of Philosophy
SubjectPain - Pathophysiology
Dept/ProgramAnaesthesiology
Persistent Identifierhttp://hdl.handle.net/10722/225202

 

DC FieldValueLanguage
dc.contributor.authorLuo, Xin-
dc.contributor.author羅昕-
dc.date.accessioned2016-04-28T06:50:47Z-
dc.date.available2016-04-28T06:50:47Z-
dc.date.issued2015-
dc.identifier.citationLuo, X. [羅昕]. (2015). The role of CXCL12/CXCR4 axis in central mechanisms of pathological pain. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b5736685-
dc.identifier.urihttp://hdl.handle.net/10722/225202-
dc.description.abstractPathological pain is a disease induced by abnormal pain perception under various pathological conditions, and the central mechanisms contribute to the chronification of pain symptom. Axis consisting of chemokine C-X-C motif ligand 12 (CXCL12) and its receptor chemokine C-X-C motif receptor 4 (CXCR4) is considered an emerging neuromodulator. However, the function of CXCL12/CXCR4 axis in the central mechanisms of pathological pain, especially neuropathic pain, and the mechanisms underlying its roles were still under investigation. The present study firstly explored the role of central CXCL12/CXCR4 axis in the pathophysiology of neuropathic pain. In this study, the pharmacologic effects of a single intrathecal injection of a CXCR4 antagonist (AMD3100) were assessed in a mouse model of peripheral neuropathic pain (PNP) developed using partial sciatic nerve ligation (pSNL). The results showed that, in the pSNL model, AMD3100 attenuated the development and maintenance of mechanical allodynia in a dose-dependent way without impairing motor function. It was further showed that AMD3100 downregulated the spinal levels of p65, phosphorylated-JNK1and phosphorylated-p38 in pSNL-injured mice on post-operative day (POD) 7as determined by western blotting. It was also found that the mRNA level of substance P was decreased while the mRNA levels of adrenomedullin and intercellular adhesion molecule was increased in the ipsilateral spinal cord of pSNL-injured mice with the intrathecal injection of AMD3100on POD 7. Even CXCL12/CXCR4 axis was shown to contribute to various pathological pain conditions, especially neuropathic pain, although the common mechanisms for its rolein the central pain perception were not known. The second study unveiled that the glial-glial crosstalk might account for the involvement of CXCL12/CXCR4 axis in the pathogenesis of neuropathic pain. In this study, two mouse models of neuropathic pain, pSNL model and chronic post-ischemia pain (CPIP) model, were used. It was found that CXCL12was mainly expressed in astrocyte, whereas CXCR4 in both astrocyte and microglia in spinal cord dorsal horn of naïve mice. In the pSNL or CPIP model, the spinal level of CXCL12 was upregulated in astrocyte on POD3. The combined intrathecal injection of CXCL12 with minocycline (microglia inhibitor) or AMD3100, but not fluorocitrate (astrocyte inhibitor), attenuated CXCL12-induced mechanical allodynia. Furthermore, AMD3465 or AMD3100 (CXCR4 antagonists), being administered daily at1 hour before surgery and up to POD 3, delayed the development of mechanical allodynia in the two animal pain models. Moreover, intrathecal AMD3100 decreased mRNA levels of pro-inflammatory cytokines (IL-6,IL-1βand TNFα) but did not affect those of CGRP, prodynorphin or Substance P in two pain models on POD 3. In conclusion, the studies related to my PhD thesis demonstrates that central CXCL12/CXCR4 axis contributes to the pathophysiology of neuropathic pain via glial mechanisms and might offer insights for further research on the roles and mechanisms of CXCL12/CXCR4 axis in the pain perception.-
dc.languageeng-
dc.publisherThe University of Hong Kong (Pokfulam, Hong Kong)-
dc.relation.ispartofHKU Theses Online (HKUTO)-
dc.rightsThe author retains all proprietary rights, (such as patent rights) and the right to use in future works.-
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.subject.lcshPain - Pathophysiology-
dc.titleThe role of CXCL12/CXCR4 axis in central mechanisms of pathological pain-
dc.typePG_Thesis-
dc.identifier.hkulb5736685-
dc.description.thesisnameDoctor of Philosophy-
dc.description.thesislevelDoctoral-
dc.description.thesisdisciplineAnaesthesiology-
dc.description.naturepublished_or_final_version-

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