Serotonin receptor 1A-modulated dephosphorylation of glycine receptor α3. A new molecular mechanism of breathing control for compensation of opioid-induced respiratory depression without loss of analgesia

To control the breathing rhythm the medullary respiratory network generates periodic salvo activities for inspiration, post-inspiration and expiration. These are under permanent modulatory control by serotonergic neurons of the raphe which governs the degree of phosphorylation of the inhibitory glycine receptor alpha 3. The specific activation of serotonin receptor type 1A (5-HTR1A), which is strongly expressed in the respiratory neurons, functions via inhibition of adenylate cyclase and the resulting reduction of the intracellular cAMP level and a gradual dephosphorylation of the glycine receptor type alpha 3 (GlyR alpha 3). This 5-HTR1A-GlyR alpha 3 signal pathway is independent of the A mu-opioidergic transduction pathway and via a synaptic inhibition caused by an increase in GlyR alpha 3 stimulates a disinhibition of some target neurons not only from excitatory but also from inhibitory neurons. Our physiological investigations show that this 5-HTR1A-GlyR alpha 3 modulation allows treatment of respiratory depression due to opioids without affecting the desired analgesic effects of opioids. The molecular mechanism presented here opens new pharmacological possibilities to treat opioid-induced respiratory depression and respiratory disorders due to disturbed inhibitory synaptic transmission, such as hyperekplexia.