Endogenous opioids and the development of the mammalian respiratory control network

It is well known that exogenous opioids such as morphine and fentanyl can depress breathing by inhibiting brainstem breathing control circuit activity. However, the role of endogenous opioids in breathing control is less clear. Endogenous opioid peptides and opioid receptors are expressed within the embryonic brainstem at the same time as when respiratory rhythm-generating neurons begin to mature. However, the extent to which endogenous opioids participate in respiratory control maturation is not known. Therefore, our goal is to review the current state of knowledge for the role of endogenous opioids in breathing control development. We set the stage by reviewing how endogenous opioid peptides regulate breathing in young and adult mammals. We describe the prenatal and postnatal development of endogenous opioid peptides and receptors in relation to breathing development. In addition, we review the effects of exogenous opioids on breathing during early life and identify areas in need of further study. We also broadly describe pain circuitry development to compare the opioid influence on nociception with how opioids impact breathing. We map the locations of endogenous opioid peptide production in the adult and developing brainstem respiratory network. Last, we propose clinical breathing conditions that may involve the endogenous opioid system. Given advances in tools for detecting endogenous opioid peptide release and the evidence reviewed herein, future research will yield new discoveries in the role of endogenous opioids in breathing across the lifespan.