A synthetic peptide, derived from neurotoxin GsMTx4, acts as a non-opioid analgesic to alleviate mechanical and neuropathic pain through the TRPV4 channel.

ShaoXi KE; Ping DONG; Yi MEI; JiaQi WANG; Mingxi TANG; Wanxin SU; JingJing WANG; Chen CHEN; Xiaohui WANG; JunWei JI; XinRan ZHUANG; ShuangShuang YANG; Yun ZHANG; Linda M BOLAND; Meng CUI; Masahiro SOKABE; Zhe ZHANG; QiongYao TANG

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A synthetic peptide, derived from neurotoxin GsMTx4, acts as a non-opioid analgesic to alleviate mechanical and neuropathic pain through the TRPV4 channel.

Author: ShaoXi KE ¹ ; Ping DONG ¹ ; Yi MEI ¹ ; JiaQi WANG ¹ ; Mingxi TANG ² ; Wanxin SU ¹ ; JingJing WANG ¹ ; Chen CHEN ¹ ; Xiaohui WANG ¹ ; JunWei JI ¹ ; XinRan ZHUANG ¹ ; ShuangShuang YANG ¹ ; Yun ZHANG ¹ ; Linda M BOLAND ³ ; Meng CUI ⁴ ; Masahiro SOKABE ⁵ ; Zhe ZHANG ¹ ; QiongYao TANG ¹
Author Information

1. Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou 221004, China.
2. Department of Pathology, Yaan People's Hospital (Yaan Hospital of West China Hospital of Sichuan University), Ya'an 625000, China.
3. Department of Biology, University of Richmond, Richmond, VA 23173, USA.
4. Department of Pharmaceutical Sciences, Northeastern University School of Pharmacy, Boston, MA 02115, USA.
5. Mechanobiology Laboratory, Nagoya University, Graduate School of Medicine, Nagoya 464-8601, Japan.
Publication Type:Journal Article
Keywords: Mechanical pain; Mechanosensitive channel; Non-opioid analgesic; Pain; Peptide; TRPV4; Tolerance addiction
From: Acta Pharmaceutica Sinica B 2025;15(3):1447-1462
CountryChina
Language:English
Abstract: Mechanical pain is one of the most common causes of clinical pain, but there remains a lack of effective treatment for debilitating mechanical and chronic forms of neuropathic pain. Recently, neurotoxin GsMTx4, a selective mechanosensitive (MS) channel inhibitor, has been found to be effective, while the underlying mechanism remains elusive. Here, with multiple rodent pain models, we demonstrated that a GsMTx4-based 17-residue peptide, which we call P10581, was able to reduce mechanical hyperalgesia and neuropathic pain. The analgesic effects of P10581 can be as strong as morphine but is not toxic in animal models. The anti-hyperalgesic effect of the peptide was resistant to naloxone (an μ-opioid receptor antagonist) and showed no side effects of morphine, including tolerance, motor impairment, and conditioned place preference. Pharmacological inhibition of TRPV4 by P10581 in a heterogeneous expression system, combined with the use of Trpv4 knockout mice indicates that TRPV4 channels may act as the potential target for the analgesic effect of P10581. Our study identified a potential drug for curing mechanical pain and exposed its mechanism.