Use of preproenkephalin knockout mice and selective inhibitors of enkephalinases to investigate the role of enkephalins in various behaviours

Abstract

The pharmacological effects induced by dual inhibitors acting on both NEP and APN are mainly due to the protection of the endogenous enkephalins at supraspinal and peripheral levels. It could be speculated that the residual effects observed in Penk1-/- mice after RB101 administration could be due to the direct action of other opioid peptides or through an indirect effect involving the protection of other peptide substrates of NEP or APN, as substance P or angiotensin.

TGF-β and Opioid Receptor Signaling Crosstalk Results in Improvement of Endogenous and Exogenous Opioid Analgesia under Pathological Pain Conditions

“…Downstream transduction of TGF-␤ signals after ligand binding is prevented by the kinase-deficient decoy-receptor BAMBI (Onichtchouk et al, 1999). Deletion of the BAMBI gene has constituted an effective strategy for unraveling the involvement of the TGF-␤ family in the control of pain states.…”

“…Adenylyl cyclase is a major intracellular effector linked to opioid receptor activity whose inhibition by agonists results in reduced cAMP production (Law et al, 2000;Valdizán et al, 2012). This pathway plays a crucial role in antinociception mediated by opioid drugs and other pharmacological agents (Kim et al, 2006;Pierre et al, 2009). Here we show that, after SNI, the inhibitory effects of the -agonist DAMGO and the ␦-agonist DPDPE on forskolin-induced cAMP accumulation were significantly enhanced in BAMBI-KO mice, at a time point at which, ) or with RB101 (filled circles) 30 min before performing the test.…”

“…The signaling capability of TGF-␤ is negatively modulated by the transmembrane protein BAMBI (BMP and activin membranebound inhibitor), a pseudoreceptor that is structurally similar to type I TGF-␤-receptors but lacks the kinase domain required for phosphorylation of Smad transcription factors (Onichtchouk et al, 1999). In a previous report from our group, deletion of BAMBI reveals a key inhibitory influence of TGF-␤ signaling on physiological nociception and in models of inflammatory and neuropathic pathological pain (Tramullas et al, 2010).…”

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

“…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).…”

Potentiation of the control of pain by endogenous enkephalins through inhibition of their enzymatic inactivation, a new approach towards physiological analgesics

“…La seconde était de s'assurer de la spécificité des inhibiteurs mixtes, en d'autres termes que les enképhalines étaient les substrats sélectifs de ces inhibiteurs et donc seuls responsables de l'action analgésique de ceux-ci. Cela a été parfaitement confirmé par utilisation de souris avec invalidation de la préproenképhaline dont la douleur provoquée n'est plus du tout sensible aux inhibiteurs [14]. Dans ce test de la plaque chaude, le Debio 0827 induit chez la souris une réponse antinociceptive dose-dépen-dante dont l'intensité par voie intraveineuse (DA50 = 1,6 mg/kg) est voisine de celle de la morphine (DA50 = 1,4 mg/kg).…”