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Prostaglandin D2 contributes to cisplatin-induced neuropathic pain in rats via DP2 receptor in the spinal cord

Korean Journal of Pain 2021년 34권 1호 p.27 ~ 34
Li Yaqun, 김웅모, 김승훈, 유현응, 강동호, 이형곤, 최정일, 윤명하,
소속 상세정보
 ( Li Yaqun ) - Chonnam National University Medical School Chonnam National University Hospital Department of Anesthesiology and Pain Medicine
김웅모 ( Kim Woong-Mo ) - Chonnam National University Medical School Chonnam National University Hospital Department of Anesthesiology and Pain Medicine
김승훈 ( Kim Seung-Hoon ) - Chonnam National University Medical School Chonnam National University Hospital Department of Anesthesiology and Pain Medicine
유현응 ( You Hyun-Eung ) - Chonnam National University Hwasun Hospital Department of Anesthesiology and Pain Medicine
강동호 ( Kang Dong-Ho ) - Chonnam National University Medical School Chonnam National University Hospital Department of Anesthesiology and Pain Medicine
이형곤 ( Lee Hyung-Gon ) - Chonnam National University Medical School Chonnam National University Hospital Department of Anesthesiology and Pain Medicine
최정일 ( Choi Jeong-Il ) - Chonnam National University Medical School Chonnam National University Hospital Department of Anesthesiology and Pain Medicine
윤명하 ( Yoon Myung-Ha ) - Chonnam National University Medical School Chonnam National University Hospital Department of Anesthesiology and Pain Medicine

Abstract


Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a major reason for stopping or changing anticancer therapy. Among the proposed pathomechanisms underlying CIPN, proinflammatory processes have attracted increasing attention. Here we assessed the role of prostaglandin D2 (PGD2) signaling in cisplatin-induced neuropathic pain.

Methods: CIPN was induced by intraperitoneal administration of cisplatin 2 mg/kg for 4 consecutive days using adult male Sprague-Dawley rats. PGD2 receptor DP1 and/or DP2 antagonists were administered intrathecally and the paw withdrawal thresholds were measured using von Frey filaments. Spinal expression of DP1, DP2, hematopoietic PGD synthase (H-PGDS), and lipocalin PGD synthase (L-PGDS) proteins were analyzed by western blotting.

Results: The DP1 and DP2 antagonist AMG 853 and the selective DP2 antagonist CAY10471, but not the DP1 antagonist MK0524, significantly increased the paw withdrawal threshold compared to vehicle controls (P = 0.004 and P < 0.001, respectively). Western blotting analyses revealed comparable protein expression levels in DP1 and DP2 in the spinal cord. In the CIPN group the protein expression level of L-PGDS, but not of H-PGDS, was significantly increased compared to the control group (P < 0.001).

Conclusions: The findings presented here indicate that enhanced PGD2 signaling, via upregulation of L-PGDS in the spinal cord, contributes to mechanical allodynia via DP2 receptors in a cisplatin-induced neuropathic pain model in rats, and that a blockade of DP2 receptor activation may present a novel therapeutic target for managing CIPN.

키워드

Chemoradiotherapy; Cisplatin; Hyperalgesia; Inflammation; Lipocalins; Neuralgia; Peripheral Nervous System Diseases; Prostaglandin D2; Spinal Cord

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