Inhibitory Effect of Endomorphin-2 Binding to the μ-Opioid Receptor in the Rat Pre-Botzinger Complex on the Breathing Activity

Opiates are commonly used analgesics that often cause clinical respiratory depression. However, their underlying mechanisms remain unclear. Endomorphin-2 (EM2) is a novel, endogenous tetrapeptide opioid with very high affinity and selectivity for the mu-opioid receptor (MOR). The pre-Botzinger complex (pre-BotC) is considered the center of respiratory rhythm generation, and the synaptic connections in this region are essential for respiratory rhythm. The present study identified EM2-like immunoreactive (LI) axonal terminals in the pre-BotC of adult rats. Some EM2-LI axonal terminals made principally symmetric synapses with neurokinin 1 receptor (NK1R)-LI or MOR-LI neuronal dendritic processes in the pre-BotC. Unilateral microinjection of EM2 into the pre-BotC decreased breathing frequency and amplitude. A prior microinjection of the selective MOR antagonist beta-funaltrexamine (beta-FNA) into the pre-BotC prevented the effects of EM2. The present results suggest that EM2-LI axonal terminals modulate NK1R-expressing neurons in the pre-BotC and that EM2 plays a role in respiratory depression through MORs in the pre-BotC.