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Activation of Brainstem mu‐Opioid Receptors (mORs) Increases Respiratory‐Related Motor Burst Amplitude in Neonatal Rat Brainstem‐Spinal Cord Preparations

Mu‐opioid receptors (mORs) located on brainstem respiratory neurons are part of an intricate peptidergic neuromodulatory system that regulates breathing. The endogenous role of mORs in respiratory motor control, however, is poorly understood. To explore this question, very low (nanomolar) concentrations of mOR agonist drugs were bath‐applied to neonatal rat (P1‐P3) brainstem‐spinal cord preparations while measuring respiratory‐related motor output from spinal C4‐C5 rootlets containing phrenic motor neuron axons. When DAMGO (synthetic mOR agonist) or endomorphin‐2 (endogenous mOR ligand) were bath‐applied for 15 min at 20‐100 nM, respiratory motor burst amplitude increased dramatically with a modest decrease in burst frequency. Burst amplitude facilitated by 45 ± 38% and 32 ± 24% (mean ± stdev) above baseline for 50 nM DAMGO (n=8) and 100 nM endomorphin‐2 (n=10), respectively (p<0.001). To test whether respiratory motor output on thoracic ventral roots was altered by mOR activation, brainstem‐spinal cord preparations were isolated to include spinal segments C1‐T8. Bath‐applied DAMGO (50 nM) induced burst amplitude facilitation on thoracic roots T4‐T6 and cervical roots C4‐C5 by 62 ± 19% and 38 ± 36%, respectively (p<0.012). To test whether mOR‐induced burst facilitation is due to brainstem or spinal mechanisms, a split‐bath chamber with a barrier at C1‐C2 was used to separately bathe the brainstem and spinal cord compartments. DAMGO (50 nM) application to the spinal cord (C2‐C8) had little effect on respiratory motor output measured from C4‐C5 rootlets, whereas DAMGO application to the brainstem increased C4‐C5 motor output by 34 ± 19% (p<0.004). These data suggest that mOR activation in the brainstem can transform the respiratory network to produce a motor pattern with decreased frequency balanced by increased amplitude, with relatively little change in overall neural output. Given that mOR‐induced facilitation was observed in both cervical and thoracic motor neuron pools, we hypothesize that burst amplitude facilitation is due to mOR activation on rhythm‐generating neurons or premotor neurons in the brainstem. This study reveals that endogenous mOR activation modulates the neural control of breathing in a manner that is potentially different from respiratory depression, which is more commonly associated with opioids.