{
  "abstract": "Background: Opioid use disorder is associated with persistent alterations in mesolimbic dopamine (DA) circuits, but the circuit- and neuromodulatory mechanisms driving this plasticity remain unclear. Lateral hypothalamic orexin/dynorphin (LHox/dyn) neurons provide dense input to the ventral tegmental area (VTA), where orexin and dynorphin exert opposing actions via orexin 1 receptor (Ox1R) and kappa-opioid (KOR) receptors, respectively. Here, we investigated how opioid dependence alters the selective contributions of optically driven LHox/dyn release on the firing of VTA DA neurons that project to the basolateral amygdala (BLA) or the lateral nucleus accumbens shell (lAcbSh). Methods: We measured the effects optogenetic activation of the LHox/dyn input on VTA DA neuronal activity with retrogradely labeled projection targets after repeated morphine or saline injections or fentanyl self-administration. We used fiber photometry to measure how the LHox/dyn input to the VTA influences dopamine in the BLA in opioid-dependent mice. Results: We found that in saline-treated mice, LHox/dyn predominantly inhibited BLA-projecting VTA DA neurons via KOR signaling. Remarkably, opioids, morphine or fentanyl, shifted the neuromodulatory capacity of LHox/dyn input to BLA-projecting VTA DA neurons from inhibitory to excitatory. This was due to increased dynorphin release in the VTA, leading to reduced function of KORs on BLA-projecting VTA DA neurons. This led to increased BLA DA, which typically encodes the emotional and associative salience of reward-related cues in opioid dependent mice. Conclusions: Together, we define a mechanism of how LHox/dyn corelease independently neuromodulates VTA projections, and how removal of a KOR brake leads to enhanced neuromodulatory activity of dopamine projections to the BLA.",
  "abstract_shown": true,
  "affiliations": [
    "University of Calgary"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 5,
  "authors": [
    {
      "name": "A. Mohammadkhani"
    },
    {
      "name": "H. Semizeh"
    },
    {
      "name": "I. V. Ifionu"
    },
    {
      "name": "M. Qiao"
    },
    {
      "affs": [
        0
      ],
      "name": "S. L. Borgland"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/23f7ajy1twmwb.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.10.24.761541",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.10.24.761541v1.full",
  "id": "23f7ajy1twmwb",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.10.24.761541v1",
  "language": null,
  "licence": "CC-BY-NC",
  "licence_label": "CC BY-NC",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "neuroscience"
    ],
    [
      "openalex",
      "2804|Neurotransmitter Receptor Influence on Behavior"
    ]
  ],
  "openalex": "W7224101331",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.10.24.761541v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-24",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/23f7ajy1twmwb.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:30:00Z",
      "native_id": "10.64898/2026.10.24.761541",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.10.24.761541v1"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:neuroscience",
      "subfield": "neuroscience"
    }
  ],
  "title": "Divergent roles of orexin and dynorphin in modulating VTA dopamine projections to the BLA after morphine exposure",
  "title_text": "Divergent roles of orexin and dynorphin in modulating VTA dopamine projections to the BLA after morphine exposure",
  "type": "preprint",
  "updated_at": "2026-10-30T12:30:00Z",
  "url": "https://research.draconitic.com/paper/23f7ajy1twmwb",
  "venue": "bioRxiv",
  "versions": []
}