23: T1-11 mediates substance P-dependent antisngceptive/antinociceptive signaling in chronic muscle pain

Topic: Basic Science
Subtopic: Non-specific to any diagnosis (including studies in healthy animals), Assessment and Measurement of Pain/Nociception, Drug development, Behavioral studies

Background and Aims: Chronic muscle pain is a prevalent and debilitating symptom across multiple diseases and impairs quality of life. However, currently available analgesics often provide limited efficacy, particularly for sng, which may persist or worsen despite partial pain relief. These limitations highlight an urgent need for effective therapeutics targeting sng/pain. In acid-induced fibromyalgia mouse model, substance P signaling from muscle afferent terminals suppresses sngceptor excitability and prevents mechanical hyperalgesia. These findings suggest that peripheral substance P signaling is a promising therapeutic target. Here, we aim to identify active components from Chinese medicines that modulate substance P–mediated antinociceptive signaling in fibromyalgia models.

Methods: Drug candidate : T1-11, an adenosine analogue isolated from a Chinese herb Gastrodia elata
Animal models for pain : Three mouse models of fibromyalgia were used in this study, including (1) genistein-acid intramuscular injection; (2) repeated acid intramuscular injection; (3) intermittent cold stress (ICS). Also, neuropathic pain models of chronic contraction injury (CCI) and experimental autoimmune encephalomyelitis (EAE) were used.
Pain assessments : The mechanical sensitivity of mouse is measured by von Frey test.

Results: Pharmacological approaches showed that the T1-11-indcued outward current was mediated by NK1R, potassium channel (Kv7) and adenosine receptor type 3(A3R), but not A2R. Although, T1-11 showed no binding affinity to NK1R, the protein pull-down assays demonstrated NK1R interacted with A3V1 and A3V2. In chronic pain mdoels, T1-11 showed potent antinociceptive effects on both fibromyalgia-like pain and neuropathic pain. Moreover, this antinociceptive effect of T1-11 was substance P-dependent, but opioiod-independent. In addition, we optimized T1-11 to enhance its bioactivity and reduce side effects, while overcoming its poor aqueous solubility and limitations in achievable drug concentration.

Conclusions: T1-11 selectively targets the antisngceptive/antinociceptive pathway of substance P in muscle afferent DRG neurons, as a new paradigm of peripheral analgesia against intractable chronic sng/pain.

References: 1. Cheng-Han Lee, Jiann-Her Lin, Shing-Hong Lin, Chu-Ting Chang, Yu-Wei Wu, Guy Bewick, Robert W. Banks, Stefan Gründer, Ute Hochgeschwender, Chih-Cheng Chen “A role for proprioceptors in sngception” Sci Adv 2025, 11(5): eabc5219 1-11
2. Cheng-Han Lee, Chih-Cheng Chen “Role of proprioceptors in chronic musculoskeletal pain” Exp Physiol 2024, 109(1): 45-54
3. Der-Sheng Han, Cheng-Han Lee, Yih-Dar Shieh, Ke-Vin Chang, Shing-Hong Lin, Ya-Cherng Chu, Jaw-Lin Wang, Chih-Cheng Chen “Involvement of ASIC3 and Substance P in Therapeutic Ultrasound-Mediated Analgesia in Mouse Models of Fibromyalgia” J Pain 2023, 24(8): 1493-1505.
4. Der-Sheng Han, Cheng-Han Lee, Yih-Dar Shieh, Chu-Ting Chang, Min-Hsuan Li, Ya-Cherng Chu, Jaw-Lin Wang, Ke-Vin Chang, Shing-Hong Lin, Chih-Cheng Chen “A role for substance P and acid-sensing ion channel 1a in prolotherapy with dextrose-mediated analgesia in a mouse model of chronic muscle pain” Pain 2022, 163(5): e622-e633
5. Der-Sheng Han, Cheng-Han Lee, Yih-Dar Shieh and Chih-Cheng Chen “Involvement of Substance P in the Analgesic Effect of Low-Level Laser Therapy in a Mouse Model of Chronic Widespread Muscle Pain“ Pain Med., 2019, 20:1963-1970.
6. Chia-Ching John Lin, Wei-Nan Chen, Chien-Ju Chen, Yi-Wen Lin, Andreas Zimmer, and Chih-Cheng Chen “An antinociceptive role for substance P in acid-induced chronic muscle pain” PNAS 2012, 109(2): E76-83

Presenting Author: Cheng-Han Lee
Submitting Author: Cheng-Han Lee

Senior Author: Chih-Cheng Chen

IASP 2026 Global Year theme of Neuropathic Pain: Yes

• Chia-Ching John Lin: PhD - Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
• Yu-Chia Chuang: PhD - Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
• Chih-Hung Chi: PhD - Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
• Chia-Wen Wong: MS - Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
• Wei-Na Chen: PhD - Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
• Wei-Hsin Sun: PhD - Department of Life Sciences and Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan
• Yijuang Chern: PhD - Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
• Yun-Lian Lin: PhD - National Research Institute of Chinese Medicine, Taipei 112, Taiwan
• Chih-Cheng Chen: PhD - Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan