Respiratory function in adult mice lacking the µ-opioid receptor: role of δ-receptors

Mice lacking the µ-opioid receptor (MOR) provide a unique model to determine whether opioid receptors are functionally interactive. Recent results have shown that respiratory depression produced by δ-opioid receptor agonists is suppressed in mice lacking the µ-opioid receptor. Here we investigated the involvement of µ- and δ-opioid receptors in the control of ventilation and µ/δ receptor interactions in brainstem rhythm-generating structures. Unrestrained MOR–/– and wild-type mice showed similar ventilatory patterns at rest and similar chemosensory responses to hyperoxia (100% O2), hypoxia (10% O2) or hypercapnia (5%CO2−95%O2). Blockade of δ-opioid receptors with naltrindole affected neither the ventilatory patterns nor the ventilatory responses to hypoxia in MOR–/– and wild-type mice. In-vitro, respiratory neurons were recorded in the pre-Botzinger complex of thick brainstem slices of MOR–/– and wild-type young adult mice. Respiratory frequency was not significantly different between these two groups. The δ2 receptor agonist deltorphin II (0.1–1.0 µm) decreased respiratory frequency in both groups whereas doses of the δ1 receptor agonist enkephalin[D-Pen2,5] (0.1–1.0 µm) which were ineffective in wild-type mice significantly decreased respiratory frequency in MOR–/– mice. We conclude that deletion of the µ-opioid receptor gene has no significant effect on ensuing respiratory rhythm generation, ventilatory pattern, or chemosensory control. In MOR–/– mice, the loss of respiratory-depressant effects of δ2-opioid receptor agonists previously observed in vivo does not result from a blunted response of δ receptors in brainstem rhythm-generating structures. These structures show an unaltered response to δ2-receptor agonists and an augmented response to δ1-receptor agonists.