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Spinal PKC activation - Induced neuronal HMGB1 translocation contributes to hyperalgesia in a bone cancer pain model in rats.
Exp Neurol. 2018 05; 303:80-94.EN

Abstract

Bone cancer pain (BCP) remains a serious complication of malignancy, which is an intractable clinical problem due to the gap in knowledge of its underlying mechanisms. Recent studies have demonstrated that the major involvement of neuroinflammation, particularly high-mobility group box 1 (HMGB1), which was identified as a late mediator of inflammation, in a number of pain conditions. However, the underlying mechanisms and functions of HMGB1 release in spinal cord, and its contributions to the development of BCP as well, are poorly understood. In the present study, we examined the theory that PKC activation lead to nuclear translocation and cytosolic HMGB1 secretion, which subsequently induces spinal neuro inflammatory responses (cytokine release) causing hyperalgesia. Our results showed that PKC activation and HMGB1 release in spinal neurons as well as mechanical allodynia in BCP rats, were all attenuated by intrathecal administration of the PKC inhibitor Gö6983 and aggravated by its activator PMA. Intrathecal administration of anti-HMGB1 antibody also alleviated hypersensitivity caused by BCP. Meanwhile, phospho-PKC and cellular HMGB1 were found co-localized in neurons, but not in microglia and astrocytes, of the spinal dorsal horns of tumor-bearing rats. Additionally, we found that HMGB1 translocation from nuclei to cytoplasm may be the consequence of PKC translocation into the nuclei, which occurred 9 days after tumor inoculation. Total p-HMGB1 as well as nuclear and cytoplasmic HMGB1 expression levels were tested in response to broad-spectrum PKC inhibitor Gö6983 or activator PMA in BCP rats. Together, these findings suggest that bone cancer related hyperalgesia is driven by PKC induced phosphorylation of HMGB1, which results in its translocation from the nucleus, and releasing from the cytosol of the dorsal horn, and the activation of spinal pro-inflammatory mediators.

Authors+Show Affiliations

Department of Anesthesiology, Bengbu Medical College, Bengbu 233000, China; Department of Anesthesiology and Pain Medicine, The First Affiliated Hospital of Jiaxing University, Jiaxing 314001, China.Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing 210004, China.Department of Anesthesiology and Pain Medicine, The First Affiliated Hospital of Jiaxing University, Jiaxing 314001, China.Department of Anesthesiology, Bengbu Medical College, Bengbu 233000, China.Department of Anesthesiology and Pain Medicine, The First Affiliated Hospital of Jiaxing University, Jiaxing 314001, China.Department of Anesthesiology, Bengbu Medical College, Bengbu 233000, China.Department of Anesthesiology, Bengbu Medical College, Bengbu 233000, China.Department of Anesthesiology and Pain Medicine, The First Affiliated Hospital of Jiaxing University, Jiaxing 314001, China.Department of Anesthesiology and Pain Medicine, The First Affiliated Hospital of Jiaxing University, Jiaxing 314001, China.Department of Anesthesiology and Pain Medicine, The First Affiliated Hospital of Jiaxing University, Jiaxing 314001, China. Electronic address: jxyaoming@mail.zjxu.edu.cn.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29428215

Citation

An, Kang, et al. "Spinal PKC Activation - Induced Neuronal HMGB1 Translocation Contributes to Hyperalgesia in a Bone Cancer Pain Model in Rats." Experimental Neurology, vol. 303, 2018, pp. 80-94.
An K, Rong H, Ni H, et al. Spinal PKC activation - Induced neuronal HMGB1 translocation contributes to hyperalgesia in a bone cancer pain model in rats. Exp Neurol. 2018;303:80-94.
An, K., Rong, H., Ni, H., Zhu, C., Xu, L., Liu, Q., Chen, Y., Zheng, Y., Huang, B., & Yao, M. (2018). Spinal PKC activation - Induced neuronal HMGB1 translocation contributes to hyperalgesia in a bone cancer pain model in rats. Experimental Neurology, 303, 80-94. https://doi.org/10.1016/j.expneurol.2018.02.003
An K, et al. Spinal PKC Activation - Induced Neuronal HMGB1 Translocation Contributes to Hyperalgesia in a Bone Cancer Pain Model in Rats. Exp Neurol. 2018;303:80-94. PubMed PMID: 29428215.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Spinal PKC activation - Induced neuronal HMGB1 translocation contributes to hyperalgesia in a bone cancer pain model in rats. AU - An,Kang, AU - Rong,Hui, AU - Ni,Huadong, AU - Zhu,Chunyan, AU - Xu,Longsheng, AU - Liu,Qianying, AU - Chen,Yajing, AU - Zheng,Ying, AU - Huang,Bing, AU - Yao,Ming, Y1 - 2018/02/08/ PY - 2017/09/15/received PY - 2018/01/22/revised PY - 2018/02/06/accepted PY - 2018/2/13/pubmed PY - 2018/12/21/medline PY - 2018/2/12/entrez KW - Bone cancer pain KW - High-mobility group box 1 KW - Hyperalgesia KW - PKC KW - Translocation SP - 80 EP - 94 JF - Experimental neurology JO - Exp Neurol VL - 303 N2 - Bone cancer pain (BCP) remains a serious complication of malignancy, which is an intractable clinical problem due to the gap in knowledge of its underlying mechanisms. Recent studies have demonstrated that the major involvement of neuroinflammation, particularly high-mobility group box 1 (HMGB1), which was identified as a late mediator of inflammation, in a number of pain conditions. However, the underlying mechanisms and functions of HMGB1 release in spinal cord, and its contributions to the development of BCP as well, are poorly understood. In the present study, we examined the theory that PKC activation lead to nuclear translocation and cytosolic HMGB1 secretion, which subsequently induces spinal neuro inflammatory responses (cytokine release) causing hyperalgesia. Our results showed that PKC activation and HMGB1 release in spinal neurons as well as mechanical allodynia in BCP rats, were all attenuated by intrathecal administration of the PKC inhibitor Gö6983 and aggravated by its activator PMA. Intrathecal administration of anti-HMGB1 antibody also alleviated hypersensitivity caused by BCP. Meanwhile, phospho-PKC and cellular HMGB1 were found co-localized in neurons, but not in microglia and astrocytes, of the spinal dorsal horns of tumor-bearing rats. Additionally, we found that HMGB1 translocation from nuclei to cytoplasm may be the consequence of PKC translocation into the nuclei, which occurred 9 days after tumor inoculation. Total p-HMGB1 as well as nuclear and cytoplasmic HMGB1 expression levels were tested in response to broad-spectrum PKC inhibitor Gö6983 or activator PMA in BCP rats. Together, these findings suggest that bone cancer related hyperalgesia is driven by PKC induced phosphorylation of HMGB1, which results in its translocation from the nucleus, and releasing from the cytosol of the dorsal horn, and the activation of spinal pro-inflammatory mediators. SN - 1090-2430 UR - https://www.unboundmedicine.com/medline/citation/29428215/Spinal_PKC_activation___Induced_neuronal_HMGB1_translocation_contributes_to_hyperalgesia_in_a_bone_cancer_pain_model_in_rats_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-4886(18)30043-8 DB - PRIME DP - Unbound Medicine ER -