Blockage of spinal endothelin A receptors attenuates bone cancer pain via regulation of the Akt/ERK signaling pathway in mice. (April 2018)

• Record Type: Journal Article
• Authors: Han, Ming-Ming; Yang, Cheng-Wei; Cheung, Chi-Wai; Li, Juan
• Is Part Of: Neuropeptides. Volume 68(2018)
• Page Start: 36
• Page End: 42
• Publication Date: 2018-04
• Subjects: Endothelin A receptor antagonist -- Bone cancer pain -- Signalling pathway; BCP Bone cancer pain -- ETAR endothelin A receptor -- ET-1 Endothelin-1 -- NSF number of spontaneous flinches -- PWT pain withdrawal threshold -- DRG dorsal root ganglia; Neuropeptides -- Periodicals; Neuropeptides; Neuropeptides -- Périodiques; Neuropeptides; Electronic journals; Periodicals; 572.65
• DOI: 10.1016/j.npep.2018.01.003
• Languages: English
• ISSNs: 0143-4179

Abstract

Abstract: Bone cancer pain (BCP) is a common source of pain in patients with advanced stage and metastatic cancer; however, existing treatment for this kind of pain remains deficient. Being closely related to sensory change and inflammatory pain in both the central and peripheral nervous systems, endothelin A receptor (ETAR) plays an essential role in pain processing. As a result, ETAR antagonist has been reported to alleviate both neuropathic and inflammatory pain. Thus far, the role of ETAR in the process of BCP is still ambiguous. In this study, by using a BCP mouse model, the analgesic effect and molecular mechanism of the ETAR antagonist BQ-123 was investigated. Pain sensation in the BCP mouse model was investigated by the number of spontaneous flinches (NSF) and pain withdrawal threshold (PWT), and the mechanism of BCP was assessed by measuring p-Akt, p-Akt/t-Akt, p-ERK-1/2 and p-ERK-1/2/t-ERK-1/2 levels in L4–6 segments of the spinal cord. Our results demonstrated that BCP mice showed a higher NSF and a lower PWT score than Sham mice. In addition to the development of nociceptive sensitization, p-Akt, p-Akt/t-Akt, p-ERK-1/2 and p-ERK-1/2/t-ERK-1/2 were up-regulated correspondingly in L4–6 segments of the spinal cord in BCP mice. BQ-123 treatment showed a promising analgesic effect, and the effect was correlated to the down-regulation of p-Akt, p-Akt/t-Akt, p-ERK-1/2 and p-ERK-1/2/t-ERK-1/2 in spinal cord cells. The results suggested that intrathecal administration of BQ-123 was able to relieve BCP in mice as a consequence of suppressing the Akt and ERK signalling pathways. Highlights: BCP mice developed pain-related behavioural changes. p-Akt and p-ERK up-regulated in the spinal cord in BCP mice. Intrathecal Administration of BQ-123 attenuates BCP. p-Akt and p-ERK down-regulated after BQ-123 intrathecal administrated.