Nociceptin/orphanin FQ causes non-quantal slowing of respiratory rhythm in brainstem–spinal cord preparation from newborn rat

Abstract

Nociceptin/orphanin FQ (N/OFQ) is the endogenous agonist of the N/OFQ peptide receptor, an inhibitory G protein-coupled receptor. N/OFQ acts as a neuromodulator to depress respiratory rhythm in the brainstem. Although the mechanisms of respiratory rhythm generation remain poorly understood, the pre-inspiratory neuron (Pre-I) and the pre-Bötzinger complex (preBötC) inspiratory neuron (Insp) network in the rostral ventrolateral medulla (RVLM) have been proposed to be essential for respiratory rhythm generation. Opioids presumably cause quantal slowing via selective depression of preBötC Insps. However, it is unclear whether N/OFQ depresses respiratory rhythm via the same mechanism. In this study, using in vitro newborn rat en bloc preparations, we examined the slowing pattern of N/OFQ (quantal or non-quantal) and the effects of N/OFQ on the extracellularly recorded discharge of Pre-Is and Insps in the RVLM. N/OFQ caused non-quantal slowing with a synchronous decrease in burst rates of Insps and of C4 discharge whereas the intraburst spike number in Insps remained unchanged. It also caused a significant decrease in burst rates and intraburst spike numbers in Pre-Is, while the 1:1 coupling of Pre-Is bursts to C4 bursts was preserved. When superfusate K(+) was elevated from 6.2 to 11.2mM, Pre-I activity was increasingly uncoupled from C4 bursts. After the application of N/OFQ in a high [K(+)] superfusate, the 1:1 coupling of Pre-Is to C4 bursts was restored. We conclude that N/OFQ suppresses burst and spike generation of Pre-Is, and that suppression of Pre-Is activity with synchronous coupling to the Insps network contributes to N/OFQ-induced non-quantal slowing.