# A Novel Analgesic with Reduced Side Effects and Abuse Liability Relative to Morphine, With Potential for Opioid Dependence Therapy

> **NIH VA I01** · SOUTHEAST LOUISIANA VETERANS HEALTH CARE · 2022 · —

## Abstract

Opioids acting at the mu opioid receptor (MOR) are the most effective therapy for
moderate to severe pain, but serious side effects limit their use. Abuse liability is of
particular importance. The recent epidemic of opioid abuse has produced major
medical, societal and economic problems. Additional side effects include respiratory
depression, the cause of fatal overdose, tolerance, which complicates treatment and
increases risk of side effects, and motor and cognitive impairment. Despite these and
other adverse effects, medications based on compounds discovered around 100 years
ago represent a majority of the available opioids. In an innovative approach to the
development of pain medications, we developed modifications of a natural brain peptide
that resulted in a stable, MOR-selective, highly effective analgesic with a reduction of
several side effects relative to morphine. These include reduction in a) respiratory
depression, b) impairment of motor coordination, c) tolerance and hyperalgesia, d) glial
p38/CGRP/P2X7 receptor signaling, and e) reward/abuse potential in two animal
models -conditioned place preference (CPP) and self-administration (SA) tests- that
correlate with human abuse liability. In this project we will further characterize the
effects of this lead compound, the endomorphin analog ZH853, in tests indicative of
abuse liability. These include tests of dependence (indicated by withdrawal symptoms
and aversion behaviors), and CPP and SA tests in conditions known to enhance drug-
seeking and -taking (previous opioid use and stress). A lack of rewarding properties by
ZH853 in these conditions would reinforce the likelihood that it will not be abused in
humans and that it would be useful for pain treatment of former addicts. We will also
test the possibility that ZH853 could be useful for opioid maintenance therapy for
addiction. The latter will be tested in reinstatement paradigms where CPP and SA
induced by morphine are extinguished and ZH853 is then tested for
reduction/prevention of reinstatement. We will also examine a mechanism likely to
contribute to the different, more favorable profile of ZH853: We have shown that ZH853
does not produce the glial activation shown by morphine in the spinal cord and
correlated with tolerance. We will assess whether differential glial activation in the brain
reward system contributes to the relative lack of reward (that correlates with addiction
potential) by ZH853 compared to morphine. Successful outcome of the studies would
support the concepts that ZH853: 1) has low abuse liability even under conditions
known to enhance the likelihood of drug use (previous opioid use and stress), 2) could
safely provide effective pain relief for patients previously addicted to opioids, 3) could
provide maintenance therapy for opioid addiction, and 4) is mechanistically distinct from
morphine due to its lack of activation of glia and glial-neuron plasticity in the reward
system. Together with the previously ...

## Key facts

- **NIH application ID:** 10428491
- **Project number:** 5I01BX003776-05
- **Recipient organization:** SOUTHEAST LOUISIANA VETERANS HEALTH CARE
- **Principal Investigator:** James E Zadina
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2018-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10428491

## Citation

> US National Institutes of Health, RePORTER application 10428491, A Novel Analgesic with Reduced Side Effects and Abuse Liability Relative to Morphine, With Potential for Opioid Dependence Therapy (5I01BX003776-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10428491. Licensed CC0.

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