Effects of repeated central administration of endothelin type A receptor antagonist on the development of neuropathic pain in rats

Abstract

Endothelin-1 (ET-1) predominates in the endothelin family effectively in vascular tone control, mitogenesis, and neuromodulation. Its receptors are widespread in the central nervous system (CNS) associated with endogenous pain control, suggesting an important role of ET-1 in central pain processing. This study aimed to evaluate the effect of central ET-1 on the development of neuropathic pain behaviour by repeated intrathecal administration of endothelin type A receptor (ETAR) antagonist (BQ-123) in a sciatic nerve ligation (SNL) animal model. BQ-123 was administered intrathecally to rats at dosages 15 μg, 20 μg, 25 μg, and 30 μg, daily for 3 days. Mechanical allodynia was assessed daily 30 minutes before/after injection, 1 hour after injection of BQ-123 from post-SNL day 4 to day 6, and once on day 7 (without BQ-123 administration) before rats were sacrificed. Increasing trends of mechanical threshold were observed, and they reached significance at all dosages on post-SNL day 7 (P < 0.05 at dosage 15 μg and P < 0.001 at dosages 20 μg, 25 μg, and 30 μg) in comparison to control group. BQ-123 at dosage 30 μg showed the most stable and significant mechanical threshold rise. Repeated central administration of BQ-123 alleviated mechanical allodynia after SNL. Our results provide insight into the therapeutic strategies, including timing, against neuropathic pain development with ETAR antagonist.

Figure 1

Effect of BQ-123 (15 μg, 20 μg, 25 μg, and 30 μg) on mechanical allodynia induced by sciatic nerve ligation (SNL) at 30 minutes after intrathecal administration. Drug administration started on day 4 and continued to day 6 after SNL for 3 consecutive days. Data presented as mean ± S.E.M and n = 6/group. Significance is presented as **P < 0.01 for BQ-123 20 μg group versus control group; ^# P < 0.05 and ^### P < 0.001 for BQ-123 25 μg group versus control group; ⁺⁺⁺ P < 0.001 for BQ-123 30 μg group versus control group.

Figure 2

Comparison of mechanical threshold between BQ-123 treatment groups (15 μg, 20 μg, 25 μg, and 30 μg) and control group at 1 hour after intrathecal administration. Drug administration initiated on day 4 and continued to day 6 after sciatic nerve ligation (SNL) for 3 consecutive days. Data are presented as mean ± S.E.M and n = 6/group. Significance is presented as *P < 0.05 for BQ-123 20 μg group versus control group; ^# P < 0.05 and ^## P < 0.01 for BQ-123 25 μg group versus control group; ⁺⁺ P < 0.01 and ⁺⁺⁺ P < 0.001 for BQ-123 30 μg group versus control group.

Figure 3

Comparison of mechanical threshold between BQ-123 treatment groups (15 μg, 20 μg, 25 μg, and 30 μg) and control group 30 minutes before intrathecal administration. Assessment was made on day 7 that no drug was administered. Data presented as mean ± S.E.M and n = 6/group. Significance is presented as ^∧ P < 0.05 for BQ-123 15 μg group versus control group; ***P < 0.001 for BQ-123 20 μg group versus control group; ^### P < 0.001 for BQ-123 25 μg group versus control group; ⁺⁺⁺ P < 0.001 for BQ-123 30 μg group versus control group. SNL: sciatic nerve ligation.