Korean J Pain.  2021 Jan;34(1):27-34. 10.3344/kjp.2021.34.1.27.

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

• Li Y
• Kim WM
• Kim SH
• You HE
• Kang DH
• Lee HG
• Choi JI
• Yoon MH

• KMID: 2510309
• DOI: http://doi.org/10.3344/kjp.2021.34.1.27

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 cisplatininduced 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.

Keyword

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

Figure

• 

  Fig. 1 (A) Time-response and (B) dose-response data showing the effects of the DP1 and DP2 antagonist, AMG853, on the hind paw withdrawal response in cisplatin-treated rats. Data are presented as the mechanical withdrawal thresholds in grams or the area under the time course curve (AUC) for the withdrawal threshold. Each line or bar represents the mean ± standard error of mean of 8 rats. BL: baseline value. aP < 0.05 compared to the vehicle group.

• 

  Fig. 2 (A) Time-response and (B) dose-response data showing the effects of the DP1 antagonist, MK0524, on the hind paw withdrawal response in cisplatin-treated rats. Data are presented as the mechanical withdrawal thresholds in grams or the area under the time course curve (AUC) for the withdrawal threshold. Each line or bar represents the mean ± standard error of mean of 7 rats. BL: baseline value.

• 

  Fig. 3 (A) Time-response and (B) dose-response data showing the effects of the DP2 antagonist, CAY10471, on the hind paw withdrawal response in cisplatin-treated rats. Data are presented as the mechanical withdrawal thresholds in grams or the area under the time course curves (AUC) for the withdrawal threshold. Each line or bar represents the mean ± standard error of mean of 7 rats. BL: baseline value. aP = 0.004 compared to the vehicle group. bP < 0.001 compared to the vehicle group. cP = 0.001 compared to the 3 µg dose group.

• 

  Fig. 4 Expression of (A) DP1 and (B) DP2, (C) hematopoietic prostaglandin synthase (H-PGDS), and (D) lipocalin prostaglandin synthase (L-PGDS) protein by western blotting analyses (optical density [OD]) in the spinal cord of vehicle-treated (control) or cisplatin-treated (chemotherapy-induced peripheral neuropathy [CIPN]) animals. Insets show representative western blots. Lanes 1 and 2 show vehicle- and cisplatin-treated animals, respectively. Histograms show quantification of the OD expressed as a ratio to the corresponding β-actin level. Values are means ± standard error of mean of 6 rats. aP < 0.001 compared to the vehicle group.

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