Divergent roles of orexin and dynorphin in modulating VTA dopamine projections to the BLA after morphine exposure
- 1University of Calgary
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.
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BibTeX
@misc{mohammadkhani2026divergent,
title = {{Divergent roles of orexin and dynorphin in modulating VTA dopamine projections to the BLA after morphine exposure}},
author = {A. Mohammadkhani and H. Semizeh and I. V. Ifionu and M. Qiao and S. L. Borgland},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.24.761541},
url = {https://www.biorxiv.org/content/10.64898/2026.10.24.761541v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Divergent roles of orexin and dynorphin in modulating VTA dopamine projections to the BLA after morphine exposure
AU - A. Mohammadkhani
AU - H. Semizeh
AU - I. V. Ifionu
AU - M. Qiao
AU - S. L. Borgland
PY - 2026
DA - 2026/10/24
PB - bioRxiv
DO - 10.64898/2026.10.24.761541
UR - https://www.biorxiv.org/content/10.64898/2026.10.24.761541v1
AB - 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.
ER -