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; Gregory Corder

doi:10.1038/s41467-023-41407-2

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

Nat Commun. 2023 Sep 13;14(1):5632. doi: 10.1038/s41467-023-41407-2.

Authors

Gregory J Salimando^{1

2}, Sébastien Tremblay^{1

2}, Blake A Kimmey^{1

2}, Jia Li³, Sophie A Rogers^{1

2}, Jessica A Wojick^{1

2}, Nora M McCall^{1

2}, Lisa M Wooldridge^{1

2}, Amrith Rodrigues⁴, Tito Borner^{1

5}, Kristin L Gardiner⁶, Selwyn S Jayakar⁷, Ilyas Singeç⁸, Clifford J Woolf⁷, Matthew R Hayes^{1

5}, Bart C De Jonghe^{1

5}, F Christian Bennett^{1

9}, Mariko L Bennett⁹, Julie A Blendy¹⁰, Michael L Platt^{1

2}, Kate Townsend Creasy^{4

5}, William R Renthal³, Charu Ramakrishnan¹¹, Karl Deisseroth^{12

13

14

15}, Gregory Corder^{16

17}

Affiliations

¹ Dept. of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
² Dept. of Neuroscience, Mahoney Institute for Neurosciences, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
³ Dept. of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
⁴ Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁵ Dept. of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA, USA.
⁶ Dept. of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁷ F.M. Kirby Neurobiology Center, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
⁸ Stem Cell Translation Laboratory, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA.
⁹ Division of Neurology, Dept. of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
¹⁰ Dept. of Systems Pharmacology & Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹¹ CNC Program, Stanford University, Stanford, CA, USA.
¹² CNC Program, Stanford University, Stanford, CA, USA. deissero@stanford.edu.
¹³ Dept. of Bioengineering, Stanford University, Stanford, CA, USA. deissero@stanford.edu.
¹⁴ Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA. deissero@stanford.edu.
¹⁵ Dept. of Psychiatry & Behavioral Sciences, Stanford University, Stanford, CA, USA. deissero@stanford.edu.
¹⁶ Dept. of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. gcorder@upenn.edu.
¹⁷ Dept. of Neuroscience, Mahoney Institute for Neurosciences, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. gcorder@upenn.edu.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Analgesia*
Animals
Chronic Pain*
Humans
Induced Pluripotent Stem Cells*
Macaca
Mice
Rats
Receptors, Opioid
Receptors, Opioid, mu / genetics
Transgenes

Substances

OPRM1 protein, human
Receptors, Opioid
Receptors, Opioid, mu
Oprm protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding