• Lin Zhou, Yahui Hu, Chengyuan Li, Yunyi Yan, Luyao Ao, Boyang Yu, Weirong Fang, Jihua Liu, and Yunman Li.
• State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, Nanjing 210009, PR China.
• Neuropharmacology. 2018 Jun 1; 135: 34-47.

AbstractVincristine is a commonly used chemotherapeutic drug that can produce painful peripheral neuropathy. The chemokine (C-X-C motif) ligand 1 (CXCL1) and its receptor chemokine (C-X-C motif) receptor 2 (CXCR2) may mediate the resolution of this inflammation. In this study, we investigated whether and how CXCL1 contributes to vincristine-induced pain and the underlying mechanisms of levo-corydalmine (l-CDL, a tetrahydroprotoberberine). Oxycodone hydrochloride (a semisynthetic opioid analgesic) was used as positive control in vivo experiments. The results revealed that both l-CDL and oxycodone attenuated vincristine-induced persistent pain hypersensitivity and proinflammatory factors release in mice. CXCL1 and CXCR2 were increased from 6 to 14 days after vincristine administration in the spinal cord. In addition, vincristine injection induced the phosphorylation of NFκB by activating p65/RelA. To confirm these results, we demonstrated that l-CDL controlled astrocytic-released CXCL1 by inhibiting p65/RelA activation, thus acting on the CXCR2 receptor in the spinal cord. In cultured astrocytes, TNF-α elicited marked release of the chemokine CXCL1; moreover, the release was blocked by NFκB p65 small interfering RNA, NFκB inhibitor, and was dose-dependently decreased by l-CDL. However, l-CDL had no effect on CXCL1 in response to NFκB p65-silenced. In primary neurons, l-CDL indirectly reduced an increase in CXCR2 by astrocyte-conditioned medium but did not act directly on the CXCR2 site. Taken together, our data first demonstrate that an NFκB-dependent CXCL1/CXCR2 signaling pathway is involved in vincristine-induced neuropathic pain. In addition, the present findings suggest that l-CDL likely attenuates this inflammation through down-regulation of this signaling pathway.Copyright © 2018 Elsevier Ltd. All rights reserved.

40 keywords...

hide…