Serotonin 1A receptors stabilize respiratory activity through interneuronal disinhibition

Abstract

The serotonin receptor (5-HTR) agonist 8-OH-DPAT recovers μ-opioid receptor (μ-OR)-mediated respiratory depression. However, 8-OH-DPAT activates 5-HT1A and 5-HT7 receptor subtypes (5-HT1AR, 5-HT7R) that operate antagonistically on adenylyl cyclase (AC). According to previously published data (Manzke et al. 2003), activation of an antagonistic signaling cascade can recover μ-OR-evoked respiratory depression, while analgetic effects of opioids were maintained. 5-HT1A and μ-ORs operate on synergistic signaling pathways mediating suppression of AC, while 5-HT7Rs are positively coupled to the AC through Gs-proteins. Here we report that 5-HT1A and 5-HT7Rs are strongly co-expressed in inhibitory glycine transporter 2 (GlyT2)-positive neurons of the respiratory network including the Pre-Boetzinger complex (PBC) and that their activation stimulate (5-HT1AR) or depress (5-HT7R) respiratory activity in the in situ perfused brainstem preparation. In vivo experiments confirmed that the beneficial effects of 8-OH-DPAT are exclusively mediated via 5-HT1AR activation. We conclude that 8-OH-DPAT mediates the rescue phenomenon from opioid-induced apnea without loss of analgesia through disinhibition of interneurons of the respiratory network. Funded by the CMPB Göttingen Lit.: Manzke, T et al., Science 301: 226-229, 2003