Fractalkine/CX3CR1 Contributes to Endometriosis-Induced Neuropathic Pain and Mechanical Hypersensitivity in Rats
Pain is the most severe and common symptom of endometriosis. Its underlying pathogenetic mechanism is poorly understood. Nerve sensitization is a particular research challenge, due to the limitations of general endometriosis models and sampling nerve tissue from patients. The chemokine fractalkine (...
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Frontiers Media S.A.
2018-12-01
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| Series: | Frontiers in Cellular Neuroscience |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fncel.2018.00495/full |
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| author | Zhiming Liu Zhiming Liu Sisi Chen Chunping Qiu Chunping Qiu Yaqiong Sun Wenzhi Li Wenzhi Li Jie Jiang Jun-Ming Zhang |
| author_facet | Zhiming Liu Zhiming Liu Sisi Chen Chunping Qiu Chunping Qiu Yaqiong Sun Wenzhi Li Wenzhi Li Jie Jiang Jun-Ming Zhang |
| author_sort | Zhiming Liu |
| collection | DOAJ |
| description | Pain is the most severe and common symptom of endometriosis. Its underlying pathogenetic mechanism is poorly understood. Nerve sensitization is a particular research challenge, due to the limitations of general endometriosis models and sampling nerve tissue from patients. The chemokine fractalkine (FKN) has been demonstrated to play a key role in various forms of neuropathic pain, while its role in endometriotic pain is unknown. Our study was designed to explore the function of FKN in the development and maintenance of peripheral hyperalgesia and central sensitization in endometriosis using a novel endometriosis animal model developed in our laboratory. After modeling, behavioral tests were carried out and the optimal time for molecular changes was obtained. We extracted ectopic tissues and L4–6 spinal cords to detect peripheral and central roles for FKN, respectively. To assess morphologic characteristics of endometriosis-like lesions—as well as expression and location of FKN/CX3CR1—we performed H&E staining, immunostaining, and western blotting analyses. Furthermore, inhibition of FKN expression in the spinal cord was achieved by intrathecal administration of an FKN-neutralizing antibody to demonstrate its function. Our results showed that implanted autologous uterine tissue around the sciatic nerve induced endometriosis-like lesions and produced mechanical hyperalgesia and allodynia. FKN was highly expressed on macrophages, whereas its receptor CX3CR1 was overexpressed in the myelin sheath of sciatic nerve fibers. Overexpressed FKN was also observed in neurons. CX3CR1/pp38-MAPK was upregulated in activated microglia in the spinal dorsal horn. Intrathecal administration of FKN-neutralizing antibody not only reversed the established mechanical hyperalgesia and allodynia, but also inhibited the expression of CX3CR1/pp38-MAPK in activated microglia, which was essential for the persistence of central sensitization. We concluded that the FKN/CX3CR1 signaling pathway might be one of the mechanisms of peripheral hyperalgesia in endometriosis, which requires further studies. Spinal FKN is important for the development and maintenance of central sensitization in endometriosis, and it may further serve as a novel therapeutic target to relieve persistent pain associated with endometriosis. |
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| language | English |
| last_indexed | 2024-12-12T03:09:26Z |
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| spelling | doaj.art-370e159bf87a48b982c940e03ab47b5b2022-12-22T00:40:26ZengFrontiers Media S.A.Frontiers in Cellular Neuroscience1662-51022018-12-011210.3389/fncel.2018.00495411671Fractalkine/CX3CR1 Contributes to Endometriosis-Induced Neuropathic Pain and Mechanical Hypersensitivity in RatsZhiming Liu0Zhiming Liu1Sisi Chen2Chunping Qiu3Chunping Qiu4Yaqiong Sun5Wenzhi Li6Wenzhi Li7Jie Jiang8Jun-Ming Zhang9Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, ChinaKey Laboratory of Gynecologic Oncology of Shandong Province, Qilu Hospital of Shandong University, Jinan, ChinaPain Research Center, Department of Anesthesiology, University of Cincinnati College of Medicine, Cincinnati, OH, United StatesDepartment of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, ChinaKey Laboratory of Gynecologic Oncology of Shandong Province, Qilu Hospital of Shandong University, Jinan, ChinaDepartment of Obstetrics and Gynecology, Shandong Obstetrics and Gynecology Hospital, Jinan, ChinaDepartment of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, ChinaKey Laboratory of Gynecologic Oncology of Shandong Province, Qilu Hospital of Shandong University, Jinan, ChinaDepartment of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, ChinaPain Research Center, Department of Anesthesiology, University of Cincinnati College of Medicine, Cincinnati, OH, United StatesPain is the most severe and common symptom of endometriosis. Its underlying pathogenetic mechanism is poorly understood. Nerve sensitization is a particular research challenge, due to the limitations of general endometriosis models and sampling nerve tissue from patients. The chemokine fractalkine (FKN) has been demonstrated to play a key role in various forms of neuropathic pain, while its role in endometriotic pain is unknown. Our study was designed to explore the function of FKN in the development and maintenance of peripheral hyperalgesia and central sensitization in endometriosis using a novel endometriosis animal model developed in our laboratory. After modeling, behavioral tests were carried out and the optimal time for molecular changes was obtained. We extracted ectopic tissues and L4–6 spinal cords to detect peripheral and central roles for FKN, respectively. To assess morphologic characteristics of endometriosis-like lesions—as well as expression and location of FKN/CX3CR1—we performed H&E staining, immunostaining, and western blotting analyses. Furthermore, inhibition of FKN expression in the spinal cord was achieved by intrathecal administration of an FKN-neutralizing antibody to demonstrate its function. Our results showed that implanted autologous uterine tissue around the sciatic nerve induced endometriosis-like lesions and produced mechanical hyperalgesia and allodynia. FKN was highly expressed on macrophages, whereas its receptor CX3CR1 was overexpressed in the myelin sheath of sciatic nerve fibers. Overexpressed FKN was also observed in neurons. CX3CR1/pp38-MAPK was upregulated in activated microglia in the spinal dorsal horn. Intrathecal administration of FKN-neutralizing antibody not only reversed the established mechanical hyperalgesia and allodynia, but also inhibited the expression of CX3CR1/pp38-MAPK in activated microglia, which was essential for the persistence of central sensitization. We concluded that the FKN/CX3CR1 signaling pathway might be one of the mechanisms of peripheral hyperalgesia in endometriosis, which requires further studies. Spinal FKN is important for the development and maintenance of central sensitization in endometriosis, and it may further serve as a novel therapeutic target to relieve persistent pain associated with endometriosis.https://www.frontiersin.org/article/10.3389/fncel.2018.00495/fullendometriosisfractalkineneuropathic paininflammationmicrogliaperipheral hyperalgesia |
| spellingShingle | Zhiming Liu Zhiming Liu Sisi Chen Chunping Qiu Chunping Qiu Yaqiong Sun Wenzhi Li Wenzhi Li Jie Jiang Jun-Ming Zhang Fractalkine/CX3CR1 Contributes to Endometriosis-Induced Neuropathic Pain and Mechanical Hypersensitivity in Rats Frontiers in Cellular Neuroscience endometriosis fractalkine neuropathic pain inflammation microglia peripheral hyperalgesia |
| title | Fractalkine/CX3CR1 Contributes to Endometriosis-Induced Neuropathic Pain and Mechanical Hypersensitivity in Rats |
| title_full | Fractalkine/CX3CR1 Contributes to Endometriosis-Induced Neuropathic Pain and Mechanical Hypersensitivity in Rats |
| title_fullStr | Fractalkine/CX3CR1 Contributes to Endometriosis-Induced Neuropathic Pain and Mechanical Hypersensitivity in Rats |
| title_full_unstemmed | Fractalkine/CX3CR1 Contributes to Endometriosis-Induced Neuropathic Pain and Mechanical Hypersensitivity in Rats |
| title_short | Fractalkine/CX3CR1 Contributes to Endometriosis-Induced Neuropathic Pain and Mechanical Hypersensitivity in Rats |
| title_sort | fractalkine cx3cr1 contributes to endometriosis induced neuropathic pain and mechanical hypersensitivity in rats |
| topic | endometriosis fractalkine neuropathic pain inflammation microglia peripheral hyperalgesia |
| url | https://www.frontiersin.org/article/10.3389/fncel.2018.00495/full |
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