Respiratory function in adult mice lacking the mu-opioid receptor: role ofdelta-receptors

Mice lacking the mu -opioid receptor (MOR) provide a unique model to determ ine whether opioid receptors are functionally interactive. Recent results h ave shown that respiratory depression produced by delta -opioid receptor ag onists is suppressed in mice lacking the mu -opioid receptor. Here we inves tigated the involvement of mu- and delta -opioid receptors in the control o f ventilation and mu/delta receptor interactions in brainstem rhythm-genera ting structures. Unrestrained MOR-/- and wild-type mice showed similar vent ilatory patterns at rest and similar chemosensory responses to hyperoxia (1 00% O-2), hypoxia (10% O-2) or hypercapnia (5%CO2-95%O-2). Blockade of delt a -opioid receptors with naltrindole affected neither the ventilatory patte rns 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. Respirato ry frequency was not significantly different between these two groups. The delta (2) receptor agonist deltorphin II (0.1-1.0 mum) decreased respirator y frequency in both groups whereas doses of the delta (1) receptor agonist enkephalin[D-Pen(2,5)] (0.1-1.0 mum) which were ineffective in wild-type mi ce significantly decreased respiratory frequency in MOR-/- mice. We conclud e that deletion of the mu -opioid receptor gene has no significant effect o n ensuing respiratory rhythm generation, ventilatory pattern, or chemosenso ry control. In MOR-/- mice, the loss of respiratory-depressant effects of d elta (2)-opioid receptor agonists previously observed in vivo does not resu lt from a blunted response of delta receptors in brainstem rhythm-generatin g structures. These structures show an unaltered response to delta (2)-rece ptor agonists and an augmented response to delta (1)-receptor agonists.