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Functional characterization of a novel opioid, PZM21, and its effects on the behavioural responses to morphine.

ABSTRACT: BACKGROUND AND PURPOSE:The concept of opioid ligands biased towards the G protein pathway with minimal recruitment of ?-arrestin-2 is a promising approach for the development of novel, efficient, and potentially nonaddictive opioid therapeutics. A recently discovered biased ?-opioid receptor agonist, PZM21, showed analgesic effects with reduced side effects. Here, we aimed to further investigate the behavioural and biochemical properties of PZM21. EXPERIMENT APPROACH:We evaluated antinociceptive effects of systemic and intrathecal PZM21 administration. Its addiction-like properties were determined using several behavioural approaches: conditioned place preference, locomotor sensitization, precipitated withdrawal, and self-administration. Also, effects of PZM21 on morphine-induced antinociception, tolerance, and reward were assessed. Effects of PZM21 on striatal release of monoamines were evaluated using brain microdialysis. KEY RESULTS:PZM21 caused long-lasting dose-dependent antinociception. It did not induce reward- and reinforcement-related behaviour; however, its repeated administration led to antinociceptive tolerance and naloxone-precipitated withdrawal symptoms. Pretreatment with PZM21 enhanced morphine-induced antinociception and attenuated the expression of morphine reward. In comparison to morphine, PZM21 administration induced a moderate release of dopamine and a robust release of 5-HT in the striatum. CONCLUSIONS AND IMPLICATIONS:PZM21 exhibited antinociceptive efficacy, without rewarding or reinforcing properties. However, its clinical application may be restricted, as it induces tolerance and withdrawal symptoms. Notably, its ability to diminish morphine reward implies that PZM21 may be useful in treatment of opioid use disorders.

SUBMITTER: Kudla L

PROVIDER: S-EPMC6932942 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Functional characterization of a novel opioid, PZM21, and its effects on the behavioural responses to morphine.

Kudla Lucja L Bugno Ryszard R Skupio Urszula U Wiktorowska Lucja L Solecki Wojciech W Wojtas Adam A Golembiowska Krystyna K Zádor Ferenc F Benyhe Sándor S Buda Szymon S Makuch Wioletta W Przewlocka Barbara B Bojarski Andrzej J AJ Przewlocki Ryszard R

British journal of pharmacology 20191208 23

<h4>Background and purpose</h4>The concept of opioid ligands biased towards the G protein pathway with minimal recruitment of β-arrestin-2 is a promising approach for the development of novel, efficient, and potentially nonaddictive opioid therapeutics. A recently discovered biased μ-opioid receptor agonist, PZM21, showed analgesic effects with reduced side effects. Here, we aimed to further investigate the behavioural and biochemical properties of PZM21.<h4>Experiment approach</h4>We evaluated ...[more]

PMID: 31347704

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Project description:BackgroundSingle-shot intrathecal morphine (ITM) is an effective strategy for postoperative analgesia, but there are limited data on its safety, efficacy, and relationship with functional recovery among patients undergoing pancreaticoduodenectomy.Study designThis was a retrospective review of patients undergoing pancreaticoduodenectomy from 2014 to 2020 as identified by the institutional NSQIP Hepato-pancreato-biliary database. Patients were categorized by having received no spinal analgesia, ITM, or ITM with transversus abdominus plane block (ITM+TAP). The primary outcomes were average daily pain scores from postoperative days (POD) 0 to 3, total morphine equivalents (MEQ) consumed over POD 0 to 3, and average daily inpatient MEQ from POD 4 to discharge. Secondary outcomes included the incidence of opioid related complications, length of stay, and functional recovery.ResultsA total of 233 patients with a median age of 67 years were included. Of these, 36.5% received no spinal analgesia, 49.3% received ITM, and 14.2% received ITM+TAP. Average pain scores in POD 0 to 3 were similar by mode of spinal analgesia (none [2.8], ITM [2.6], ITM+TAP [2.3]). Total MEQ consumed from POD 0 to 3 were lower for patients who received ITM (121 mg) and ITM+TAP (132 mg), compared with no spinal analgesia (232 mg) (p < 0.0001). Average daily MEQ consumption from POD 4 to discharge was lower for ITM (18 mg) and ITM+TAP (13.1 mg) cohorts compared with no spinal analgesia (32.9 mg) (p = 0.0016). Days to functional recovery and length of stay were significantly reduced for ITM and ITM+TAP compared with no spinal analgesia. These findings remained consistent through multivariate analysis, and there were no differences in opioid-related complications among cohorts.ConclusionsITM was associated with reduced early postoperative and total inpatient opioid utilization, days to functional recovery, and length of stay among patients undergoing pancreaticoduodenectomy. ITM is a safe and effective form of perioperative analgesia that may benefit patients undergoing pancreaticoduodenectomy.

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Functional characterization of a novel opioid, PZM21, and its effects on the behavioural responses to morphine.

Publications

Functional characterization of a novel opioid, PZM21, and its effects on the behavioural responses to morphine.

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