Role of the pre‐Bötzinger Complex in opioid‐induced respiratory depression in adult rats in‐vivo

Abstract

Respiratory rhythm is generated by pre‐Bötzinger Complex (PBC) neurons in‐vitro, with destruction of PBC neurons producing ataxic breathing in‐vivo. Activation of µ‐opioid receptors at the PBC decreases respiratory rate in neonatal rats in‐vitro, but the role of the PBC in opioid‐induced respiratory depression has not been tested in‐vivo. We recorded diaphragm and genioglossus (GG) muscle activities in adult rats with drugs applied to the PBC region by microdialysis probes. In anesthetized rats (n=6), application of the µ‐opioid receptor agonist fentanyl (100 µM) to the PBC decreased respiratory rate (mean = 43%, p=0.004) and GG activity (mean = 61%, p=0.007), with this depression reversed by the antagonist naloxone (100 µM). The time delay for fentanyl‐induced respiratory depression was correlated with the distance of the probe site from the PBC (r2 = 0.83). Preliminary data in 2 freely behaving rats showed that fentanyl (150 µM) at the PBC also reduced respiratory rate in non‐REM sleep (~30%) but not wakefulness (~3%). The respiratory rate depression produced by fentanyl at the PBC also occurred with subcutaneous fentanyl (0.02‐0.1 mg/kg) in anesthetized and freely behaving rats (mean decreases 30‐54%, p<0.05). These data show that opioid‐sensitive neurons in the PBC mediate suppression of respiratory rate in‐vivo, with responses to µ‐opioid receptor agonists being prominent in non‐REM sleep and anesthesia.