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

Abstract

We investigated whether the enkephalin-catabolizing enzyme inhibitors RB101 and kelatorphan, which have been shown to be potent analgesics, depress respiration as do opioid analgesics. Ventilation was measured in cats and rodents by the barometric method, in the awake state and during anesthesia. Tissue distribution of the inhibitors was either generalized (RB101, 40-160 mg/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. injection of RB101 in the fourth ventricle). RB101 did not affect ventilation in any condition tested, and large doses of kelatorphan produced a naloxone-reversible increase in ventilation and breathing frequency. Thus endogenous opioids released during conditions of normal ventilation do not exert any depressant neuromodulatory effect on this function, even when their extracellular concentrations are increased by peptidase inhibitors. The differential effect of these inhibitors on ventilation and nociception is discussed. We conclude that kelatorphan and RB101 are devoid of respiratory-depressant effects and might be interesting pharmacological alternatives to morphine and other opioid agonists.

Preventive and alleviative effects of the dual enkephalinase inhibitor (Denki) PL265 in a murine model of neuropathic pain

“…However, the role of dual enkephalinase inhibitors on the noradrenergic and serotoninergic pathways to modulate the descending pain inputs is minimized by the weak tonic release of enkephalins in the brain structures such as locus coeruleus and nucleus raphe magnus (Williams et al, 1987;Boudinot et al, 2001).…”

“…Numerous dual enkephalinase inhibitors (DENKIs) have been developed and were shown to selectively protect in vitro and in vivo the enkephalins and to be very effective on various animal models of pain . The protected enkephalins are devoid of the side-effects of morphine (Noble et al, 2008), because the recruitment of opioid receptors is restricted to enkephalin releasing synapses and ubiquitous with morphine, (Williams et al, 1987;Roques et al, 2000;Boudinot et al, 2001). Among these inhibitors, the amino-phosphinic dual inhibitor PL265 presents the advantages to act only at the peripheral level and shows a long duration of action (Bonnard et al, 2015).…”

Enkephalinase inhibitors, potential therapeutics for the future treatment of diarrhea predominant functional gastrointestinal disorders

“…Noteworthy, there was a slight decrease (around 20%) in a respiratory minute‐volume that occurred 15 min after drug administration, but it did not disturb the respiration in the long run. In awake cats, icv administration of RB101 (0.4 mg/mouse) did not influence ventilation …”

“…The antinociceptive action of this enkephalinase inhibitor during inflammation was limited to the periphery, because icv administration of naloxone‐methiodide only slightly antagonized the action of RB101 (20 mg/kg iv ) in arthritic rats . The influence of RB101 on respiration was assessed by Boudinot et al; it was revealed that this agent (100 mg/kg ip ) during 60 min observation period did not significantly affect ventilation when compared to control. Noteworthy, there was a slight decrease (around 20%) in a respiratory minute‐volume that occurred 15 min after drug administration, but it did not disturb the respiration in the long run.…”

RB101‐mediated Protection of Endogenous Opioids: Potential Therapeutic Utility?

“…RB101, over a range of antinociceptive doses, administered peripherally in awake and anesthetized mice did not alter ventilation (minute volume) even at high doses, 160 mg/kg (i.p.) (Boudinot et al 2001). In the same study, central administration of a large dose of RB101 into the fourth ventricle of awake cats also did not decrease ventilation as compared with vehicle controls.…”