Exploring opioid receptor dependent biased agonism in the PreBötzinger Complex

Respiratory depression is a hallmark of opiate overdose and is mediated by activation of μ‐opioid receptors (MORs) to suppress the drive for breathing. Agonist binding to MOR can preferentially activate Gi or β‐arrestin‐2 (β‐arr2) signaling. Although a large body of literature suggests that activation of the β‐arr2 pathway is involved with respiratory depression, emerging evidence has challenged this perspective. This raises the question of whether the development of biased agonist opiates is valuable for mitigating adverse respiratory side effects. The preBötzinger complex (preBötC) is area in the respiratory network expressing MORs and is responsible for inspiratory rhythm generation. This ongoing study examines the role of MORs biased agonism on opioid modulation of rhythmogenesis in the preBötC. Extracellular population recordings were made in preBötC slices prepared from wildtype mice and β‐arr2 knock out mice (β‐arr2−/−). No differences were observed between genotypes in the degree of inhibition caused by the opiate agonist DAMGO. Additionally, no differences were observed with Endmorphin‐2 application, an opioid receptor agonist biased for β‐arr2 signaling. These findings indicate that β‐arr2 signaling in the preBötC is not responsible for the inhibition of rhythmogenesis caused by activation of MORs. Thus, developing biased agonist opiates to mitigate depressive respiratory side effects may not be an effective strategy. Support or Funding Information NIH T32DA043469, NIH PO 1 HL 144454, NIH R01 NS10742101