Spinal PKC activation — Induced neuronal HMGB1 translocation contributes to hyperalgesia in a bone cancer pain model in rats

• Published in: Experimental neurology Vol. 303; pp. 80 - 94
• Main Authors: An, Kang, Rong, Hui, Ni, Huadong, Zhu, Chunyan, Xu, Longsheng, Liu, Qianying, Chen, Yajing, Zheng, Ying, Huang, Bing, Yao, Ming
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.05.2018
• Subjects: Animals; Bone cancer pain; Bone Neoplasms - complications; Bone Neoplasms - diagnostic imaging; Cancer Pain - complications; Cancer Pain - diagnostic imaging; Cancer Pain - etiology; Cancer Pain - pathology; Cytokines - metabolism; Disease Models, Animal; Female; Gene Expression Regulation, Neoplastic - drug effects; Gene Expression Regulation, Neoplastic - genetics; Glial Fibrillary Acidic Protein - metabolism; High-mobility group box 1; HMGB1 Protein - genetics; HMGB1 Protein - metabolism; Hyperalgesia; Hyperalgesia - etiology; Hyperalgesia - metabolism; Indoles - pharmacology; Maleimides - pharmacology; Neurons - metabolism; Pain Measurement; PKC; Protein Kinase Inhibitors - pharmacology; Protein Transport - drug effects; Protein Transport - genetics; Rats; Rats, Sprague-Dawley; Receptor for Advanced Glycation End Products - metabolism; Spinal Cord - drug effects; Spinal Cord - enzymology; Spinal Cord - pathology; Translocation; X-Rays; Translocation; High-mobility group box 1; PKC; Bone cancer pain; Hyperalgesia
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1016/j.expneurol.2018.02.003

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. •The levels of HMGB1 and related proinflammatory cytokine expression were elevated.•Nuclear HMGB1 translocation and PKC activation primarily occurred in neurons.•PKC activation caused HMGB1 translocation via a phosphorylation-dependent mechanism.•HMGB1 release enhanced the expression of proinflammatory mediators.