Low-Dose Interleukin-2 Resolves Stress-Induced Chronic Sensitization Independent of Opioid Receptor Signaling

Authors

Simoes, R. R., Kraus, S., Zhang, J., Do Nascimento, L. F., Tosh, D. K., Unsinger, J., Hotchkiss, R. S., Che, T., Jacobson, K. A., Cao, Y.-Q.

Abstract

Stress is a common trigger of headache and widespread somatic pain. Repeated exposure to stress establishes latent sensitization that is tonically suppressed by endogenous inhibitory systems. Using brain-penetrating and peripherally restricted receptor antagonists in a mouse model of repetitive restraint stress, we systematically identified these protective pathways. Peripheral kappa opioid receptors as well as GABA type A and type B (GABAA and GABAB) receptors, alongside central opioid and cannabinoid signaling, actively suppress headache-related facial mechanical hypersensitivity in stressed mice. Blocking any pathway quickly reinstated cephalic allodynia. Peripheral opioid and GABAA receptor signaling also inhibited stress-induced latent sensitization on hindpaw. In contrast, depletion of anti-inflammatory regulatory T (Treg) cells prolonged facial but not hindpaw sensitization, suggesting that Tregs preferentially limit stress-induced chronic headache. Next, we administered low-dose interleukin-2 (LD-IL-2) to stressed mice to preferentially expand and activate Treg cells. Following LD-IL-2 treatment, neither subthreshold pain triggers nor blockade of endogenous inhibitory pathways reinstated cephalic or hindpaw allodynia in either sex, indicating elimination of stress-induced sensitization. Mechanistically, LD-IL-2 acted through Treg cells to recruit multiple peripheral cytokine pathways without engaging endogenous opioid, GABA, or cannabinoid receptor signaling. Notably, LD-IL-2 was more effective than anti-CGRP (calcitonin gene-related peptide) therapy in preventing headache-related chronic sensitization in stressed mice. Collectively, these findings reveal multiple central and peripheral pathways that act concertedly to mask stress-induced latent sensitization and strongly support further evaluation of LD-IL-2 as a novel treatment for stress-induced headache and widespread pain with a distinct mechanism of action.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 07 Sep 2026.

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