Cell-type specific molecular architecture for mu opioid receptor function in pain and addiction circuits

Abstract

Opioids are potent analgesics broadly used for pain management; however, they can produce dangerous side effects including addiction and respiratory depression. These harmful effects have led to an epidemic of opioid abuse and overdose deaths, creating an urgent need for the development of both safer pain medications and treatments for opioid use disorders. Both the analgesic and addictive properties of opioids are mediated by the mu opioid receptor (MOR), making resolution of the cell types and neural circuits responsible for each of the effects of opioids a critical research goal. Single-cell RNA sequencing (scRNA-seq) technology is enabling the identification of MOR-expressing cell types throughout the nervous system, creating new opportunities for mapping distinct opioid effects onto newly discovered cell types. Here, we describe molecularly defined MOR-expressing neuronal cell types throughout the peripheral and central nervous systems and their potential contributions to opioid analgesia and addiction.

Keywords: Cell types; Mu opioid receptor; Nervous system; Opioid addiction; Opioid analgesia; Single cell RNA-Sequencing.

Fig. 1.. Historical perspective: elucidation of the expression pattern of Oprm1 and MOR.

Although radioligand binding and autoradiography studies provided the first window into the tissues and regions in which MOR was expressed, the cloning of the Oprm1 gene in 1993 allowed for a myriad of new genetics-based approaches to reappraise and refine Oprm1 and MOR distribution in tissues. Today, this rapidly expanding set of techniques, paired with high-throughput RNA-seq, enables the comprehensive elucidation of MOR expression patterns at the single cell level, in the DRG, spinal cord, and brain. (A) Timeline showing the evolution of techniques used for detection of Oprm1/MOR. (B) Table indicating Oprm1/MOR+ regions in DRG, spinal cord, and brain via these techniques. (Arttamangkul et al., 2008; Bailly et al., 2020; Ding et al., 1996; Ehrlich et al., 2019; Fritzwanker et al., 2021; Mengaziol et al., 2022; Sugino et al., 2019).

Fig. 1.. Historical perspective: elucidation of the expression pattern of Oprm1 and MOR.

Although radioligand binding and autoradiography studies provided the first window into the tissues and regions in which MOR was expressed, the cloning of the Oprm1 gene in 1993 allowed for a myriad of new genetics-based approaches to reappraise and refine Oprm1 and MOR distribution in tissues. Today, this rapidly expanding set of techniques, paired with high-throughput RNA-seq, enables the comprehensive elucidation of MOR expression patterns at the single cell level, in the DRG, spinal cord, and brain. (A) Timeline showing the evolution of techniques used for detection of Oprm1/MOR. (B) Table indicating Oprm1/MOR+ regions in DRG, spinal cord, and brain via these techniques. (Arttamangkul et al., 2008; Bailly et al., 2020; Ding et al., 1996; Ehrlich et al., 2019; Fritzwanker et al., 2021; Mengaziol et al., 2022; Sugino et al., 2019).

Fig. 1.. Historical perspective: elucidation of the expression pattern of Oprm1 and MOR.

Although radioligand binding and autoradiography studies provided the first window into the tissues and regions in which MOR was expressed, the cloning of the Oprm1 gene in 1993 allowed for a myriad of new genetics-based approaches to reappraise and refine Oprm1 and MOR distribution in tissues. Today, this rapidly expanding set of techniques, paired with high-throughput RNA-seq, enables the comprehensive elucidation of MOR expression patterns at the single cell level, in the DRG, spinal cord, and brain. (A) Timeline showing the evolution of techniques used for detection of Oprm1/MOR. (B) Table indicating Oprm1/MOR+ regions in DRG, spinal cord, and brain via these techniques. (Arttamangkul et al., 2008; Bailly et al., 2020; Ding et al., 1996; Ehrlich et al., 2019; Fritzwanker et al., 2021; Mengaziol et al., 2022; Sugino et al., 2019).

Fig. 2.. High-confidence Oprm1+/MOR + brain regions and their associated functions in opioid addiction and antinociception.

(A) Regions validated as being enriched in Oprm1 and MOR using multiple techniques are designated in gray. Functional contributions to opioid reward and dependence (green) and opioid antinociception (magenta) are indicated. (B) For regions with high-confidence MOR expression, marker genes defining Oprm1+ cell populations are indicated from both region-specific (yellow) and whole-brain (blue) scRNA-seq studies.