71: Sngception encodes internal state through stretch and asthenia independently of pain

Topic: Basic Science
Subtopic: Non-specific to any diagnosis (including studies in healthy animals), Developing methodology/technology, Pharmacological interventions, Behavioral studies

Background and Aims: Intraperitoneal irritation paradigms are widely used as preclinical models of pain, yet they evoke heterogeneous behaviors including active stretching and prolonged movement suppression that are typically interpreted as a unitary nociceptive output. Emerging evidence suggests that tissue acidosis can engage sngceptive sensory programs distinct from pain, mediated by proton-sensitive ion channels expressed in both proprioceptors and nociceptors (1). How these peripheral pathways organize stretch, asthenia, and pain-like restricted movement remains unresolved. We hypothesized that acetic acid recruits parallel internal sensory states through ASIC- and tachykinin-dependent signaling that can be behaviorally and mechanistically dissociated rather than reflecting a single pain response.

Methods: We developed a posture-resolved two-dimensional video analysis to quantify stretch, pain-like restricted movement -compact posture, and asthenia-like restricted movement -expanded posture, in freely moving mice independently of center-of-mass displacement. Behavioral responses to acetic acid were compared with reference stimuli (capsaicin, AITC, MgSO₄, and lipopolysaccharide), resolving different movement restrictions- posture agnostic asthenia vs pain-like guarding. Pharmacological manipulations included NSAIDs like diclofenac, ibuprofen, and acetaminophen; channel/receptor blockers like amiloride, ruthenium red, and RP67580. Whole-cell recordings were performed in fluorogold-labeled intraperitoneal afferents. Genetic analyses used global and conditional knockouts of ASIC1a, ASIC3, Tac1, and Tacr1 in proprioceptor- and nociceptor-enriched sensory neuron populations.

Results: Acetic acid evoked two temporally dissociable behavioral programs: an early posture-expanding stretch response and a later asthenia-like state characterized by prolonged restricted movement without guarding. Stretch did not temporally align with mouse grimace scale expression and displayed pharmacological sensitivity distinct from pain-like restricted movement. Electrophysiological and genetic analyses identified ASIC1a as a promoter of stretch, whereas ASIC3 biased output toward stretch or asthenia in a sensory population–specific manner across proprioceptors and nociceptors. Tachykinin signaling further dissociated these states: NK1 receptor antagonism reduced stretch, Tac1 deletion selectively increased asthenia-like restricted movement, and Tacr1 deletion selectively reduced pain-like restricted movement exclusively.

Conclusions: These findings demonstrate that intraperitoneal acidosis engages parallel peripheral sensory programs rather than a unitary nociceptive pain response. Stretch and asthenia emerge as distinct sngceptive behaviors organized through ASIC-dependent signaling in proprioceptors and nociceptors and modulated by tachykinin pathways. Peripheral sensory architecture, therefore, computes internal chemical state into separable behavioral outputs, reframing stretch and restricted movement as products of coordinated ASIC and tachykinin signaling rather than simple proxies for pain.

References: (1) Lee, Cheng-Han, Jiann-Her Lin, Shing-Hong Lin, Chu-Ting Chang, Yu-Wei Wu, Guy Bewick, Robert W. Banks, Stefan Gründer, Ute Hochgeschwender, and Chih-Cheng Chen. "A role for proprioceptors in sngception." Science advances 11, no. 5 (2025): eabc5219.

Presenting Author: Md Tauhid Siddiki Tomal
Submitting Author: Md Tauhid Siddiki Tomal

Senior Author: Chih-Cheng Chen

IASP 2026 Global Year theme of Neuropathic Pain: No

• Chih-Cheng Chen: PhD - Institute of Biomedical Sciences, Academia Sinica
• Cheng-Han Lee: PhD - Institute of Biomedical Sciences, Academia Sinica
• Md Tauhid Siddiki Tomal: PhD - Institute of Biomedical Sciences, Academia Sinica