Anatomical distribution of µ-opioid receptors, neurokinin-1 receptors, and vesicular glutamate transporter 2 in the mouse brainstem respiratory network.

Abstract

µ-Opioid receptors (MORs) are responsible for mediating both the analgesic and respiratory effects of opioids drugs. By binding to MORs in brainstem regions involved in controlling breathing, opioids produce respiratory depressive effects characterized by slow and shallow breathing, with potential cardiorespiratory arrest and death during overdose. To better understand the mechanisms underlying opioid-induced respiratory depression, thorough knowledge of the regions and cellular subpopulations that may be vulnerable to modulation by opioids is needed. Using in situ hybridization, we determined the distribution and co-expression of Oprm1 (gene encoding MORs) mRNA with glutamatergic (Vglut2) and neurokinin-1 receptor (Tacr1) mRNA in medullary and pontine regions involved in breathing control and modulation. We found that >50% of cells expressed Oprm1 mRNA in the preBötzinger Complex (preBötC), nucleus tractus solitarius (NTS), nucleus ambiguus (NA), locus coeruleus (LC), Kölliker-Fuse nucleus (KF), and the lateral and medial parabrachial nuclei (LBPN and MPBN, respectively). Among Tacr1 mRNA-expressing cells, >50% co-expressed Oprm1 mRNA in the preBötC, NTS, NA, Bötzinger Complex (BötC), LC, raphe magnus nucleus, KF, LPBN, and MPBN, whereas among Vglut2 mRNA-expressing cells, >50% co-expressed Oprm1 mRNA in the preBötC, NTS, NA, BötC, LC, KF, LPBN, and MPBN. Taken together, our study provides a comprehensive map of the distribution and co-expression of Oprm1, Tacr1, and Vglut2 mRNA in brainstem regions that control and modulate breathing and identifies Tacr1 and Vglut2 mRNA-expressing cells as subpopulations with potential vulnerability to modulation by opioids.