Background & Aims
Fibromyalgia, affecting 1~5% global population, is characterized by chronic widespread muscle pain, fatigue, and emotional distress. However, current drugs offer limited relief due to low efficacy and side effects. Thus, it’s urgent to understand fibromyalgia’s pathogenesis is essential for developing effective, low-side-effect analgesics.
Recent studies have suggested that the peripheral input is essential for the maintenance of fibromyalgia pain. In a mouse model of fibromyalgia induced by muscle acidosis, substance P signaling from muscle afferent terminals can silence the excitability of nociceptors and thus effectively prevent the development of acid-induced muscle mechanical hyperalgesia. This highlights the potential of targeting peripheral substance P signaling for fibromyalgia pain management.
Here, we aim to probe the effective ingredients from Chinese medicines that can act on the antinociceptive signaling of substance P in mouse models of fibromyalgia.
Methods
Chemicals: T1-11 is an adenosine analogue isolated from a Chinese medicinal herb Gastrodia elata, which is widely used for pain relief.
Electrophysiology: We used whole-cell patch clamp recordings to measure the effect of T1-11 on dissociated muscle afferent dorsal root ganglion (DRG) neurons.
Protein-protein interaction: We used protein pull down assay to determine the molecular identity of T1-11 receptors.
Pain models: 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: We used von Frey test for measuring the mechanical sensitivity of mice.
Results
Here we reported that T1-11 selectively induced an outward current (EC50 of 1.3 pM) in muscle afferent DRG neurons that also showed substance P-induced outward curents. 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.
Conclusions
Collectively, T1-11 selectively targets the antinociceptive pathway of substance P in muscle afferent DRG neurons, serving as a new paradigm of peripheral analgesia against intractable chronic pain.
References
Bredeson JD, Jarvis MF, Honore P, Surowy CS (2011) Fibromyalgia: mechanism, current treatment and animal models. Curr Pharm Biotechnol 12: 1613-1626.
Chen WN, Chen CC (2014) Acid mediates a prolonged antinocicpetion via substance P signaling in acid-induced chronic widespread pain. Mol Pain 10:30
Chen WN, Lee CH, Lin SH, Wong CW, Sun WH, Wood JN, Chen CC (2014) Roles of ASIC3, TRPV1, Nav1.8 in the transition from acute to chronic pain in a mouse model of fibromyalgia. Mol Pain 10:40
Huang NK, Chern Y, Fang JM, Lin CI, Chen WP, Lin YL (2007) Neuroprotective principles from Gastrodia elata. J Nat Prod 70: 571-574.
Lin CCJ, Chen WN, Chen CJ, Lin YW, Zimmer A, Chen CC (2012) An antinociceptive role for substance P in acid-induced chronic muscle pain. Proc Natl Acad Sci USA 109: E76-E83.
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Presenting Author
Cheng-Han Lee
Poster Authors
Cheng-Han Lee
PhD
Institute of Biomedical Sciences, Academia Sinica, Taiwan
Lead Author
Topics
- Treatment/Management: Pharmacology: Non-opioid