Fentanyl and neostigmine delivered to mouse prefrontal cortex differentially alter breathing

Opioids impair many functions modulated by the prefrontal cortex (PFC), including wakefulness, cognition, and breathing. In contrast, cholinergic activity in the PFC increases wakefulness. This study tested the hypothesis that microinjecting the opioid fentanyl and the acetylcholinesterase inhibitor neostigmine into the PFC of awake C57BL/6J male mice (n = 27) alters breathing. The lateral and medial PFC were unilaterally microinjected with saline (control) and fentanyl. The medial PFC received additional microinjections of neostigmine. The results show that fentanyl caused site-specific changes in breathing. Fentanyl delivered to the lateral PFC significantly decreased minute ventilation variability, whereas fentanyl delivered to the medial PFC significantly increased tidal volume and duty cycle. Neostigmine microinjected into the medial PFC significantly increased respiratory rate, tidal volume, and minute ventilation. A final series of experiments revealed that decreased minute ventilation caused by systemic fentanyl administration was mitigated by PFC microinjection of neostigmine.