17: Efficacy and Safety of Orally Active ?2?-1 C-Terminal Peptides in Neuropathic Pain

Topic: Basic Science
Subtopic: Pain category (ICD-11), Chronic neuropathic pain, , , , , , , , , , Pharmacological interventions

Background and Aims: Treatment for chronic neuropathic pain remains a major therapeutic challenge. Gabapentinoids (gabapentin and pregabalin) are commonly used as first-line therapy for neuropathic pain and primarily target α2δ-1, which interacts with NMDA and AMPA receptors. However, their clinical efficacy is often insufficient for many patients. Also, α2δ-1 may interact with many proteins via its N-terminal VWA domain. Moreover, the use of gabapentinoids is limited by adverse effects such as gait disturbances and ataxia, which are mediated through α2δ-2. To overcome these limitations, we have developed chemically modified α2δ-1 C-terminal peptides that retain the biological activity and are suitable for oral administration.

Methods: Behavioral and nociceptive tests in mice and rats subjected to peripheral nerve injury.

Results: When administered subcutaneously or orally via gavage at doses of 1–5 mg/kg, these α2δ-1 C-terminal peptides rapidly reversed tactile allodynia as well as mechanical and thermal hyperalgesia induced by nerve injury in both mice and rats, with effects lasting 2–5 hours. Furthermore, the peptides significantly reduced the nerve injury–induced increase in α2δ-1 interaction with NMDA receptors in the mouse spinal cord. Notably, they did not impair beam-walking performance or open-field locomotor activity in mice.

Conclusions: These findings demonstrate the feasibility and therapeutic potential of orally administered α2δ-1 C-terminal peptides, which appear to offer superior efficacy and fewer adverse effects compared to gabapentinoids for the treatment of neuropathic pain.

References: 1. Chen J, Li L, Chen SR, Chen H, Xie JD, Sirrieh RE, Jayaraman V, Pan HL. The α2δ 1–NMDA receptor complex is critically involved in neuropathic pain development and gabapentin therapeutic actions. Cell Rep 2018;22:2307-2321.
2. Li L, Chen SR, Zhou MH, Wang L, Li DP, Chen H, Lee G, Jayaraman V, Pan HL. α2δ 1 switches the phenotype of synaptic AMPA receptors by physically disrupting heteromeric subunit assembly. Cell Rep 2021;36:109396.
3. Zhou MH, Chen SR, Jin D, Huang Y, Chen H, Chen G, Yan J, Pan HL. Spinal α2δ 1 induces GluA3 degradation to regulate assembly of calcium-permeable AMPA receptors and pain hypersensitivity. J Clin Invest 2025;Oct 23:e193349.

Presenting Author: Hui-Lin Pan
Submitting Author: Hui-Lin Pan

Senior Author: Shao-Rui Chen

IASP 2026 Global Year theme of Neuropathic Pain: Yes

• Shao-Rui Chen: MD - MD Anderson Cancer Center