Discriminative Stimulus and Low Abuse Liability Effects of Novel Endomorphin Analogs Suggest a Potential Treatment Indication for Opioid Use Disorder

Abstract

Opioid dependence can be difficult to manage using existing pharmacotherapies. A long-acting opioid with low abuse liability that substitutes for a shorter-acting opioid may improve treatment of opioid use disorders (OUDs). We recently characterized an endomorphin (EM) analog (ZH853) that produced a longer duration of antinociception compared with morphine, but did not produce self-administration or several other adverse effects preclinically. Here, we further characterized ZH853 in tests of antinociception, abuse liability, and drug discrimination. A conditioned place preference (CPP) procedure, that included a locomotor activity assessment, was used to test abuse liability in rats. Subsequently, dopamine (DA) cell-somas located in the ventral tegmental area (VTA) from these rats were assessed by size using immunohistochemistry and Stereo Investigator software. A hot-plate antinociception test in male and female mice confirmed central penetration. Morphine-substitution effects of several EM analogs (ZH850, ZH831, and ZH853) were tested in a drug discrimination (DD) procedure in rats. Morphine produced dose-dependent CPP and locomotor sensitization and reduced the size of DA cell somas in VTA, whereas ZH853 did not produce any of these effects relative to control. The antinociceptive effects of ZH853 were m-receptor selective since b-funaltrexamine antagonized these effects. Rats responded on a morphinetrained lever when injected with ZH831 and ZH853 during DD experiments. The favorable morphine-substitution effects of these EM analogs relative to their low abuse liability indicate promising novel compounds that may improve treatment of OUD. SIGNIFICANCE STATEMENT In this experiment, we investigated the preclinical effects of novel endomorphin analogs for use as substitution therapies for opioid use disorder, a problem that has contributed to an opioid overdose epidemic. Several endomorphin analogs substituted for morphine without producing adverse effects, including reward behaviors associated with abuse liability. These compounds have the potential to become important additional tools to treat opioid use disorders.

Endomorphin analog exhibited superiority in alleviating neuropathic hyperalgesia via weak activation of NMDA receptors

“…In 1997, Zadina et al discovered a class of endogenous peptides named endomorphin‐1 (EM‐1) and endomorphin‐2 (Zadina, Hackler, Ge, & Kastin, 1997). In addition to their analgesic function, endomorphins have an advantage over traditional opioids, such as morphine, with respect to many side effects, such as abuse liability (Codd, Carson, & Colburn, 2009; Nilges et al., 2019), respiratory depression (Zadina et al., 2016), tolerance (Wang et al., 2015), motor impairment (Feehan, Morgenweck, Zhang, Amgott‐Kwan, & Zadina, 2017b), and gastrointestinal function (Czapla & Zadina, 2005; Sobczak, Salaga, Storr, & Fichna, 2014; Wang, Qiu, et al., 2017). However, endomorphins have many problems, such as difficulty passing through the blood–brain barrier, poor enzymatic stability, and short duration of action, which limit their clinical application (Liu et al., 2017).…”

Novel endomorphin analogues CEMR‐1 and CEMR‐2 produce potent and long‐lasting antinociception with a favourable side effect profile at the spinal level

“…It was reported that a series of cyclized endomorphin analogues, particularly ZH853, displayed equal or greater potency and effectiveness compared with morphine in multiple pain models (Feehan et al, 2017). Together with substantially reduced opioid‐like side effects, these compounds showed great promise for treatment of opioid use disorders (Nilges et al, 2019; Zadina et al, 2016). Additionally, the development of multifunctional and multivalent opioid ligands can simultaneously activate multiple receptors, which facilitates to enhance the analgesic activity with a favourable side effect profile (Cunningham et al, 2019; Günther et al, 2018; Hruby, 2019).…”

Peptidomimetics and Their Applications for Opioid Peptide Drug Discovery

“…However, their low ability to penetrate the BBB and low metabolic stability prohibit therapeutic uses as analgesics, and therefore significant efforts have been made to improve metabolic stability and to obtain longer lasting antinociceptive effects through various modifications [ 26 , 27 ]. Cyclic EM-1 analogs such as ZH853 (Tyr-c[ D Lys-Trp-Phe-Glu]-Gly-NH 2 ) are recent discoveries showing longer duration of action and effective antinociception in multiple pain models with reduced adverse side effects [ 28 , 29 , 30 ].…”

“…administrations of cyclic EM-2 analogs (Tyr-c 2,5 [ D Lys-Phe(F/2,4-difluoro)-Tyr-Gly]) exhibited potent analgesic effects indicating the potential brain uptake, and the structural analyses using NMR spectroscopy suggested that a trans conformation of the backbone between positions 2 and 3 is critical for affinity, selectivity, and functional activity at the MOR. An extended structure of EM-1, ZH853 (Tyr-c[ D Lys-Trp-Phe-Glu]-Gly-NH 2 ) is a recent success showing high potential as a therapeutic agent for various pain states, including neuropathic pain [ 28 , 30 , 228 ]. Another EM analog, Tyr-c 2,5 (-SCH 2 S-)[ D Cys-Phe-2-Nal-Cys]-NH 2 showed a MOR/KOR agonist and DOR partial agonist/antagonist profile with a similar affinity at MOR and DOR [ 229 ].…”