Effects of the potent analgesic enkephalin-catabolizing enzyme inhibitors RB101 and kelatorphan on respiration

We investigated whether the enkephalin-catabolizing enzyme inhibitors RB101 and kelatorphan, which have been shown to be potent analgesics, depress re spiration as do opioid analgesics. Ventilation was measured in cats and rod ents by the barometric method, in the awake state and during anesthesia. Ti ssue distribution of the inhibitors was either generalized (RB101, 40-160 m g/kg i.p.), largely restricted by the blood-brain barrier to the periphery (kelatorphan, 0.7-20 mg/kg i.v.), or restricted to the brainstem (i.c.v. in jection of RE101 in the fourth ventricle). RE101 did not affect ventilation in any condition tested, and large doses of kelatorphan produced a naloxon e-reversible increase in ventilation and breathing frequency. Thus endogeno us opioids released during conditions of normal ventilation do not exert an y depressant neuromodulatory effect on this function, even when their extra cellular concentrations are increased by peptidase inhibitors. The differen tial effect of these inhibitors on ventilation and nociception is discussed . We conclude that kelatorphan and RB101 are devoid of respiratory-depressa nt effects and might be interesting pharmacological alternatives to morphin e and other opioid agonists. (C) 2001 International Association for the Stu dy of Pain. Published by Elsevier Science B.V. All rights reserved.