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

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.

SUBMITTER: Salimando GJ

PROVIDER: S-EPMC10499891 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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

Salimando Gregory J GJ Tremblay Sébastien S Kimmey Blake A BA Li Jia J Rogers Sophie A SA Wojick Jessica A JA McCall Nora M NM Wooldridge Lisa M LM Rodrigues Amrith A Borner Tito T Gardiner Kristin L KL Jayakar Selwyn S SS Singeç Ilyas I Woolf Clifford J CJ Hayes Matthew R MR De Jonghe Bart C BC Bennett F Christian FC Bennett Mariko L ML Blendy Julie A JA Platt Michael L ML Creasy Kate Townsend KT Renthal William R WR Ramakrishnan Charu C Deisseroth Karl K Corder Gregory G

Nature communications 20230913 1

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 ...[more]

PMID: 37704594

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Project description:INTRODUCTION:The perioperative pain experience shows great interindividual variability and is difficult to predict. The mu-1 opioid receptor gene (OPRM1) is known to play an important role in opioid-pain pathways. Since deoxyribonucleic acid (DNA) methylation is a potent repressor of gene expression, DNA methylation was evaluated at the OPRM1 promoter, as a predictor of preoperative, acute, and chronic postsurgical pain (CPSP). METHODS:A prospective observational cohort study was conducted in 133 adolescents with idiopathic scoliosis undergoing spine fusion under standard protocols. Data regarding pain, opioid consumption, anxiety, and catastrophizing (using validated questionnaires) were collected before and 2-3 months postsurgery. Outcomes evaluated were preoperative pain, acute postoperative pain (area under curve [AUC] for pain scores over 48 hours), and CPSP (numerical rating scale >3/10 at 2-3 months postsurgery). Blood samples collected preoperatively were analyzed for DNA methylation by pyrosequencing of 22 CpG sites at the OPRM1 gene promoter. The association of each pain outcome with the methylation percentage of each CpG site was assessed using multivariable regression, adjusting for significant (P<0.05) nongenetic variables. RESULTS:Majority (83%) of the patients reported no pain preoperatively, while CPSP occurred in 36% of the subjects (44/121). Regression on dichotomized preoperative pain outcome showed association with methylation at six CpG sites (1, 3, 4, 9, 11, and 17) (P<0.05). Methylation at CpG sites 4, 17, and 18 was associated with higher AUC after adjusting for opioid consumption and preoperative pain score (P<0.05). After adjusting for postoperative opioid consumption and preoperative pain score, methylation at CpG sites 13 and 22 was associated with CPSP (P<0.05). DISCUSSION:Novel CPSP biomarkers were identified in an active regulatory region of the OPRM1 gene that binds multiple transcription factors. Inhibition of binding by DNA methylation potentially decreases the OPRM1 gene expression, leading to a decreased response to endogenous and exogenous opioids, and an increased pain experience.

Dataset Information

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

Publications

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

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