Human OPRM1 and murine Oprm1 promoter driven viral constructs for genetic access to μ-opioidergic cell types

Gregory J. Salimando, Sébastien Tremblay, Blake A. Kimmey, Jia Li, Sophie A. Rogers, Jessica A. Wojick, Nora M. McCall, Lisa M. Wooldridge, Amrith Rodrigues, Tito Borner, Kristin L. Gardiner, Selwyn S. Jayakar, Ilyas Singeç, Clifford J. Woolf, Matthew R. Hayes, Bart C. De Jonghe, F. Christian Bennett, Mariko L. Bennett, Julie A. Blendy, Michael L. Platt, Kate Townsend Creasy, William R. Renthal, Charu Ramakrishnan, Karl Deisseroth () and Gregory Corder ()
Additional contact information
Gregory J. Salimando: University of Pennsylvania
Sébastien Tremblay: University of Pennsylvania
Blake A. Kimmey: University of Pennsylvania
Jia Li: Brigham and Women’s Hospital and Harvard Medical School
Sophie A. Rogers: University of Pennsylvania
Jessica A. Wojick: University of Pennsylvania
Nora M. McCall: University of Pennsylvania
Lisa M. Wooldridge: University of Pennsylvania
Amrith Rodrigues: University of Pennsylvania
Tito Borner: University of Pennsylvania
Kristin L. Gardiner: University of Pennsylvania
Selwyn S. Jayakar: Boston Children’s Hospital and Harvard Medical School
Ilyas Singeç: National Institutes of Health
Clifford J. Woolf: Boston Children’s Hospital and Harvard Medical School
Matthew R. Hayes: University of Pennsylvania
Bart C. De Jonghe: University of Pennsylvania
F. Christian Bennett: University of Pennsylvania
Mariko L. Bennett: Children’s Hospital of Philadelphia
Julie A. Blendy: University of Pennsylvania
Michael L. Platt: University of Pennsylvania
Kate Townsend Creasy: University of Pennsylvania
William R. Renthal: Brigham and Women’s Hospital and Harvard Medical School
Charu Ramakrishnan: Stanford University
Karl Deisseroth: Stanford University
Gregory Corder: University of Pennsylvania

Nature Communications, 2023, vol. 14, issue 1, 1-24

Abstract: Abstract With concurrent global epidemics of chronic pain and opioid use disorders, there is a critical need to identify, target and manipulate specific cell populations expressing the mu-opioid receptor (MOR). However, available tools and transgenic models for gaining long-term genetic access to MOR+ neural cell types and circuits involved in modulating pain, analgesia and addiction across species are limited. To address this, we developed a catalog of MOR promoter (MORp) based constructs packaged into adeno-associated viral vectors that drive transgene expression in MOR+ cells. MORp constructs designed from promoter regions upstream of the mouse Oprm1 gene (mMORp) were validated for transduction efficiency and selectivity in endogenous MOR+ neurons in the brain, spinal cord, and periphery of mice, with additional studies revealing robust expression in rats, shrews, and human induced pluripotent stem cell (iPSC)-derived nociceptors. The use of mMORp for in vivo fiber photometry, behavioral chemogenetics, and intersectional genetic strategies is also demonstrated. Lastly, a human designed MORp (hMORp) efficiently transduced macaque cortical OPRM1+ cells. Together, our MORp toolkit provides researchers cell type specific genetic access to target and functionally manipulate mu-opioidergic neurons across a range of vertebrate species and translational models for pain, addiction, and neuropsychiatric disorders.

Date: 2023
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DOI: 10.1038/s41467-023-41407-2

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