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

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 (<em>MORp</em>) based constructs packaged into adeno-associated viral vectors that drive transgene expression in MOR+ cells. <em>MORp</em> constructs designed from promoter regions upstream of the mouse <em>Oprm1</em> gene (<em>mMORp</em>) 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 <em>mMORp</em> for <em>in vivo</em> fiber photometry, behavioral chemogenetics, and intersectional genetic strategies is also demonstrated. Lastly, a human designed <em>MORp</em> (<em>hMORp</em>) efficiently transduced macaque cortical <em>OPRM1</em>+ cells. Together, our <em>MORp</em> 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.