Cheng Songxia, Ding Jiali, Xu Biao, Wang Yan, Shen Xiaoyu, Xia Yanhua, Wu Lei, Wei Jie
Department of Physiology, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi Province, 330006, PR China.
Key Laboratory of Preclinical Study for New Drugs of Gansu Province, and Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu Province, 730000, PR China.
Eur J Pharmacol. 2025 Jan 5;986:177148. doi: 10.1016/j.ejphar.2024.177148. Epub 2024 Nov 23.
Burn induced-pain (BIP) is one of the most common pain symptoms, which seriously affects the quality of sufferer life. Researches show that multi-targeted drug therapies offer superior efficacy and fewer side effects compared to single-target drug therapies. Consequently, in this study, we developed G(1-5)-EM2, a multi-targeted peptide designed to target μ-opioid receptor and the growth hormone secretagogue receptor 1α (GHS-R1α), and explored its antinociceptive effects on burn injury pain. Calcium mobilization experiments revealed that G(1-5)-EM2 demonstrated weak multi-agonist activities to μ-opioid receptor and κ-opioid receptor as well as GHS-R1α in vitro. Near-infrared fluorescence imaging experiments demonstrated that G(1-5)-EM2 could penetrate the blood-brain barrier (BBB) and access the brain following intravenous injection. The enzymatic stability of G(1-5)-EM2 was significantly enhanced compared to EM2. Our results indicated that intrathecal administration of G(1-5)-EM2 mitigated mechanical allodynia and thermal hyperalgesia in BIP. These antinociceptive effects of G(1-5)-EM2 were partially mediated through μ-opioid receptor and GHS-R1α. Moreover, intrathecal administration of G(1-5)-EM2 significantly decreased burn-induced up-regulation of phosphorylated p38 MAPK, phosphorylated NF-κBp65 and TRPV1 in the ipsilateral spinal cord, reduced the levels of IL-1β, IL-6 and TNF-α in serum, and enhanced wound healing in burned skin. Repeated intrathecal administration of G(1-5)-EM2 produced a non-tolerance-forming antinociception in BIP. These results suggest that the multi-targeted peptide G(1-5)-EM2 exhibits a novel role in alleviating BIP with fewer side effects and may represent a promising strategy for developing new analgesic drugs.
烧伤诱导性疼痛（BIP）是最常见的疼痛症状之一，严重影响患者的生活质量。研究表明，与单靶点药物疗法相比，多靶点药物疗法疗效更佳且副作用更少。因此，在本研究中，我们开发了G(1-5)-EM2，一种旨在靶向μ-阿片受体和生长激素促分泌素受体1α（GHS-R1α）的多靶点肽，并探究其对烧伤疼痛的镇痛作用。钙动员实验表明，G(1-5)-EM2在体外对μ-阿片受体、κ-阿片受体以及GHS-R1α表现出较弱的多激动剂活性。近红外荧光成像实验表明，静脉注射后G(1-5)-EM2能够穿透血脑屏障（BBB）并进入大脑。与EM2相比，G(1-5)-EM2的酶稳定性显著增强。我们的结果表明，鞘内注射G(1-5)-EM2可减轻BIP中的机械性异常性疼痛和热痛觉过敏。G(1-5)-EM2的这些镇痛作用部分是通过μ-阿片受体和GHS-R1α介导的。此外，鞘内注射G(1-5)-EM2可显著降低烧伤诱导的同侧脊髓中磷酸化p38 MAPK、磷酸化NF-κBp65和TRPV1的上调，降低血清中IL-1β、IL-6和TNF-α的水平，并促进烧伤皮肤的伤口愈合。重复鞘内注射G(1-5)-EM2在BIP中产生无耐受性形成的镇痛作用。这些结果表明，多靶点肽G(1-5)-EM2在减轻BIP方面具有新作用且副作用较少，可能代表了开发新型镇痛药的一种有前景的策略。
