{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "Washington University School of Medicine in St. Louis"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 10,
  "authors": [
    {
      "name": "R. R. Simoes"
    },
    {
      "name": "S. Kraus"
    },
    {
      "name": "J. Zhang"
    },
    {
      "name": "L. F. Do Nascimento"
    },
    {
      "name": "D. K. Tosh"
    },
    {
      "name": "J. Unsinger"
    },
    {
      "name": "R. S. Hotchkiss"
    },
    {
      "name": "T. Che"
    },
    {
      "name": "K. A. Jacobson"
    },
    {
      "affs": [
        0
      ],
      "name": "Y.-Q. Cao"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/5etmpxjn58xbx.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.01.748528",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.09.01.748528v1.full",
  "id": "5etmpxjn58xbx",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.09.01.748528v1",
  "language": null,
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "neuroscience"
    ],
    [
      "openalex",
      "2737|Pain Mechanisms and Treatments"
    ]
  ],
  "openalex": "W7210282047",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.09.01.748528v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-01",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/5etmpxjn58xbx.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:19:40Z",
      "native_id": "10.64898/2026.09.01.748528",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.09.01.748528v1"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:neuroscience",
      "subfield": "neuroscience"
    }
  ],
  "title": "Low-Dose Interleukin-2 Resolves Stress-Induced Chronic Sensitization Independent of Opioid Receptor Signaling",
  "title_text": "Low-Dose Interleukin-2 Resolves Stress-Induced Chronic Sensitization Independent of Opioid Receptor Signaling",
  "type": "preprint",
  "updated_at": "2026-10-30T12:19:40Z",
  "url": "https://research.draconitic.com/paper/5etmpxjn58xbx",
  "venue": "bioRxiv",
  "versions": []
}