Actions of opioids on respiratory activity via activation of brainstem mu-, delta- and kappa-receptors; an in vitro study.

Opioid-induced respiratory depression is well documented. However, exact sites of action and mechanisms for opioid-induced effects on respiration have not yet been elucidated. The present study was carried out on isolated brainstem-spinal cord preparations from newborn rats in order to explore the opioid activity on brainstem mu-, delta- and kappa-receptors. The brainstem-spinal cord was isolated from 0- to 4-day-old Sprague-Dawley rats. The preparation was perfused with artificial cerebrospinal fluid (28.5 degrees C) equilibrated with 95% O2 and 5% CO2 at a pH of 7.4. Neuronal respiratory activity was recorded from the ventrolateral part of the medulla oblongata and efferent impulses from C4 or C5 ventral roots. Effects of the mu-receptor agonist DAGO, the delta-receptor agonist DPDPE and the kappa-receptor agonist U50,488 on respiratory frequency (fR), inspiratory time (Ti) and peak integrated C4 amplitude (Int[C4]) were measured. In addition, the effect of pre-treatment with the mu1 receptor antagonist naloxanazine (35 mg/kg, subcutaneous injection) was evaluated. DAGO reduced fR and Ti in a concentration-dependent manner and caused a reduction of Int(C4) at high concentrations (10 microM). The mu1 receptor antagonist naloxanazine shifted the fR concentration-response curve for DAGO to the right (P < 0.05). DPDPE had no effect on respiratory activities whereas U50,488, like DAGO, reduced fR and Int(C4) in a concentration-dependent manner. It was concluded that mu-opioid receptors, including the mu1 were involved in fR reduction whereas kappa-opioid receptors were involved in reduction of both fR and respiratory amplitude. Delta-opioid receptors do not seem to participate in respiratory modulation at this age.