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Discovery of non-opioid peptides that selectively relieve mechanical pain in rodents through inhibition of TRPV4 channels

Acta Pharmacologica Sinica (2026)Cite this article

Abstract

Mechanical hyperalgesia is a primary symptom of clinical pain; there remains a therapeutic challenge for severe mechanical and chronic forms of neuropathic pain. The 34-amino-acid neuropeptide GsMTx4, isolated from Tarantula spatulata, was identified as a selective inhibitor of mechanosensitive channels and shown to reduce mechanical hyperalgesia and neuropathic pain in rats. We previously reported two types (type I and type II) of short peptides derived from GsMTx4 that mimicked the inhibitory action of GsMTx4 on a mechanosensitive BK (SAKca) channel. In this study, we investigated whether these short peptides alleviate mechanical hypersensitivity, a major symptom of neuropathic pain. The synthetic type I peptide 01 (Pept 01) was derived from loop2+loop3 of GsMTx4, whereas type II Pept 02, Pept 03 and, Pept 04 were derived from loop 2 of GsMTx4. Carrageenan-induced inflammatory pain was induced in rats and mice, while the chronic constriction nerve injury (CCI) model was established in rats. We showed that administration of short peptides (270 μg/kg, i.p.) selectively inhibited mechanical pain in rats but failed to impact thermal or cold hyperalgesia. Interestingly, the antihyperalgesic effects of these peptides were comparable to those of morphine; however, they were resistant to the μ-opioid receptor antagonist naloxone and lacked morphine-induced side effects, e.g., tolerance and conditioned place preference (CPP). Among them, Pept 03, which contained only one Trp (Trp1) at the head and an additional Arg (Arg11, corresponding to Arg18 in GsMTx4) at the end of the peptide, most potently alleviated mechanical hyperalgesia. Genetic deletion of the TRPV4 gene in mice mostly abolished the analgesic effect of Pept 03. In oocytes expressing TRPV4 channels, application of Pept 03 or Pept 01 inhibited GSK101- or hypotonicity-activated TRPV4 currents in a dose-dependent manner. These results suggest that TRPV4 channels may serve as a direct target for the short peptides in alleviating mechanical pain. This study identifies several natural toxin-based peptides as promising non-opioid analgesics, paving the way for the development of selective and potent painkillers to treat mechanical pain.

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Fig. 1: The synthetic peptide 01 (Pept 01, type I), derived from loop2 + loop3 of GsMTx4, reduces mechanical pain in both rats and mice.
Fig. 2: The important residues for Pept 01 critical for its analgesic effect in rats.
Fig. 3: The synthetic peptides derived from loop2 of GsMTx4 sustain the essential antihyperalgesic effect of the parent peptide on mechanical hyperalgesia.
Fig. 4: Important charged residues (Lys/Asp/Arg) that are critical for the antihyperalgesic effect of Pept 03 in rats.
Fig. 5: Important cysteine (Cys10) and hydrophobic (Trp1) residues in Pept 03, which are essential for its analgesic effect.
Fig. 6: Repeated injections of Pept 03, the most potent peptide identified, do not develop analgesic tolerance and show even more potent effect when compared with morphine in both inflammatory and neuropathic pain models.
Fig. 7: Pept3 does not produce CPP and exerts potent resistance to naloxone.
Fig. 8: Genetic deletion of the TRPV4–gene in mice mostly abolishes the analgesic effects of Type II peptides.
Fig. 9: Pept 03 inhibits TRPV4 currents activated by TRPV4-selective activator or hypotonicity in oocytes.

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Acknowledgements

We would like to thank Raymond Zhang for his help with the pain behavior test, data analysis, and grammar check for the final version. We thank Prof. Atsuko Mizuno (Jichi Medical University, Japan) for Trpv4 KO mice, Dr. Fan Yang (Zhejiang University, China) for providing the TRPV4 cDNA plasmids. We are also grateful to Dr. Linda Boland (University of Richmond, USA) for the good suggestion and English editing at the earlier stage. This work was supported by NSFC grants (81450064, 82371233) to QYT and NSFC grants (81471314, 81671090) to ZZ, Luzhou Science and Technology Bureau (2021-SYF-28) and Southwest Medical University of China (2021ZKMS033) grants to MXT, Key Project in Sichuan province department of education to MXT (16ZA0196), and Jiangsu specially appointed professorship to QYT and ZZ.

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  1. These authors contributed equally: Ping Dong, Qing-ke Fan, Shao-xi Ke, Jia-qi Wang, Yi Mei, Yi-tong Ding

Authors and Affiliations

  1. Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, 221004, China

    Ping Dong, Qing-ke Fan, Shao-xi Ke, Jia-qi Wang, Yi Mei, Yi-tong Ding, Jie Xu, Nan Zhou, Yuan-yuan Xu, Jing-jing Wang, Chen Chen, Xiao-hui Wang, Zhe Zhang & Qiong-yao Tang

  2. Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 201801, China

    Ping Dong

  3. The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310007, China

    Shao-xi Ke

  4. Department of Pathology, Yaan People’s Hospital (Yaan Hospital of West China Hospital of Sichuan University), Ya-an, 625000, China

    Jing Wang & Ming-xi Tang

  5. Department of Pharmaceutical Sciences and the Center for Drug Discovery, School of Pharmacy and Pharmaceutical Sciences, Bouvé College of Health Sciences, Northeastern University, Boston, 02115, MA, USA

    Meng Cui

  6. Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China

    Yi-mei Du

  7. Mechanobiology Laboratory, Nagoya University, Graduate School of Medicine, Nagoya, 464-8601, Japan

    Masahiro Sokabe

  8. Human Information Systems Lab, Kanazawa Institute of Technology, Hakusan, 924-0838, Japan

    Masahiro Sokabe

  9. NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, 221004, China

    Zhe Zhang & Qiong-yao Tang

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Contributions

PD, QKF, SXK, JQW, YM, JW, YTD, YYX, JJW, CC, and XHW performed research and data analysis; XJ, NZ, and MC contributed to MD simulations. YMD provides the TRPV4-KO mice. MS, MXT, ZZ, and QYT designed the experiment and supervised experiments. MXT, ZZ, and QYT wrote the original draft.

Corresponding authors

Correspondence to Yi-mei Du, Masahiro Sokabe, Ming-xi Tang, Zhe Zhang or Qiong-yao Tang.

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The authors declare no competing interests. Qiong-yao Tang, Zhe Zhang, Ming-xi Tang, Ping Dong, and Shao-xi Ke have applied for two patents related to this study.

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Dong, P., Fan, Qk., Ke, Sx. et al. Discovery of non-opioid peptides that selectively relieve mechanical pain in rodents through inhibition of TRPV4 channels. Acta Pharmacol Sin (2026). https://doi.org/10.1038/s41401-025-01698-1

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