Naderi Amirreza, Taketani Yukako, Wang Shudan, Kahale Francesca, Yung Ann, Surico Pier Luigi, Chen Yihe, Dana Reza
Department of Ophthalmology, Harvard Medical School, Schepens Eye Research Institute of Massachusetts Eye and Ear, Boston, MA, USA.
Pain Rep. 2025 Jan 17;10(1):e1232. doi: 10.1097/PR9.0000000000001232. eCollection 2025 Feb.
Ocular pain is a common complaint to eye care providers, associated with a variety of ocular conditions, among which dry eye disease (DED) is affecting millions of people worldwide. Despite being highly prevalent, ocular pain is not managed adequately in the clinic.
The aim of this study was to investigate the analgesic potential of neurokinin-1 receptor (NK1R) antagonism in DED.
Dry eye disease was induced in mice, and an NK1R antagonist L-733,060 was topically administered twice daily throughout the study for 14 days. Hyperalgesia and allodynia were assessed using the eye-wiping test and palpebral ratio measurements. Corneas were collected for measuring substance P (SP) levels by enzyme-linked immunosorbent assay (ELISA) and imaging nerves by immunostaining. Trigeminal ganglions (TG) were collected to determine SP levels by ELISA and transient receptor potential cation channel subfamily V member 1 (TRPV1), transient receptor potential cation channel subfamily M (melastatin) member 8, c-Fos, and activating transcription factor 3 (ATF3) mRNA levels by real-time polymerase chain reaction.
Treating DED mice with L-733,060 resulted in a significant reduction in eye wipe behavior, a significant increase in palpebral ratio, and significant decreases in SP levels in both the cornea and TG compared with the vehicle-treated group. In addition, NK1R antagonist treatment significantly suppressed the upregulation of TRPV1, ATF3, and c-Fos and prevented corneal nerve loss.
Neurokinin-1 receptor antagonism effectively reduced ocular nociception, decreased neuronal activation, and preserved corneal nerves in mice with DED. These findings suggest that blockade of SP signaling pathway is a promising therapeutic strategy for managing DED pain.
眼痛是眼科护理人员常见的主诉，与多种眼部疾病相关，其中干眼症（DED）在全球影响着数百万人。尽管眼痛非常普遍，但在临床上并未得到充分治疗。
本研究旨在探讨神经激肽-1受体（NK1R）拮抗剂在干眼症中的镇痛潜力。
在小鼠中诱导干眼症，并在整个研究过程中每天局部应用NK1R拮抗剂L-733,060两次，持续14天。使用擦眼试验和睑裂比例测量评估痛觉过敏和异常性疼痛。收集角膜，通过酶联免疫吸附测定（ELISA）测量P物质（SP）水平，并通过免疫染色对神经进行成像。收集三叉神经节，通过ELISA测定SP水平，并通过实时聚合酶链反应测定瞬时受体电位阳离子通道亚家族V成员1（TRPV1）、瞬时受体电位阳离子通道亚家族M（褪黑素）成员8、c-Fos和激活转录因子3（ATF3）的mRNA水平。
与载体处理组相比，用L-733,060治疗干眼症小鼠可导致擦眼行为显著减少；睑裂比例显著增加；角膜和三叉神经节中的SP水平显著降低。此外，NK1R拮抗剂治疗可显著抑制TRPV1、ATF3和c-Fos的上调，并防止角膜神经损伤。
神经激肽-1受体拮抗剂可有效减轻干眼症小鼠的眼部伤害感受，减少神经元激活，并保留角膜神经。这些发现表明，阻断SP信号通路是治疗干眼症疼痛的一种有前景的治疗策略。
