Actions of opioids on respiratory activity via activation of brainstem μ-, δ- and κ-receptors; an in vitro study

Abstract

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 μ-, δ- and κ-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°C) equilibrated with 95% O 2 and 5% CO 2 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 μ-receptor agonist DAGO, the δ-receptor agonist DPDPE and the κ-receptor agonist U50,488 on respiratory frequency ( f R), inspiratory time ( T i) and peak integrated C4 amplitude ( Int C4) were measured. In addition, the effect of pre-treatment with the μ 1 receptor antagonist naloxanazine (35 mg/kg, subcutaneous injection) was evaluated. DAGO reduced f R and T i in a concentration-dependent manner and caused a reduction of Int C4 at high concentrations (10 μM). The μ 1 receptor antagonist naloxanazine shifted the f R concentration–response curve for DAGO to the right ( P<0.05). DPDPE had no effect on respiratory activities whereas U50,488, like DAGO, reduced f R and Int C4 in a concentration-dependent manner. It was concluded that μ-opioid receptors, including the μ 1 were involved in f R reduction whereas κ-opioid receptors were involved in reduction of both f R and respiratory amplitude. δ-Opioid receptors do not seem to participate in respiratory modulation at this age.