A GPR55 Receptor Agonist Reduced Morphine Reward and Physical Dependence in Mice | Research

The takeaway

The atypical cannabinoid O-1602, which activates the GPR55 receptor, reduced both the rewarding effects and physical dependence symptoms of morphine in mice.

Readers interested in the intersection of cannabinoid and opioid pharmacology, or in new approaches to opioid dependence.

GPR55 agonist reduced both morphine reward and physical withdrawal symptoms

What the researchers found

Researchers tested whether O-1602, a compound that activates the GPR55 receptor (sometimes called a third cannabinoid receptor), could affect morphine reward and dependence in mice.

In a conditioned place preference test, O-1602 at lower doses (0.2 and 1 mg/kg) reduced the acquisition of morphine reward, meaning mice spent less time in the chamber associated with morphine. At all three doses tested, O-1602 also reduced the expression of established morphine preference.

For physical dependence, O-1602 at the highest dose (5 mg/kg) significantly reduced withdrawal symptoms including jumping and diarrhea when naloxone-precipitated withdrawal was triggered after repeated morphine administration. The highest dose also increased locomotor activity on its own.

Why it matters

Opioid dependence remains a major health challenge. Finding that a GPR55 agonist can reduce both the rewarding effects and physical dependence aspects of morphine opens a potential new avenue for addressing opioid use disorder through a cannabinoid-related receptor that is distinct from CB1 and CB2.

The numbers in context

O-1602 at 0.2 and 1 mg/kg reduced acquisition of morphine CPP. All three doses (0.2, 1, 5 mg/kg) reduced expression of morphine CPP. O-1602 at 5 mg/kg reduced jumping and diarrhea during naloxone-precipitated morphine withdrawal. The 5 mg/kg dose increased locomotor activity.

How the study worked

Male mice were tested in a biased conditioned place preference model using morphine (40 mg/kg). O-1602 was tested at 0.2, 1, and 5 mg/kg for effects on acquisition and expression of morphine preference. For physical dependence, mice received escalating morphine doses over three days, and withdrawal was triggered with naloxone. Locomotor activity was recorded throughout.

What this study cannot tell us

This was a mouse study with a relatively simple behavioral paradigm. The highest effective dose (5 mg/kg) also increased locomotor activity, which could confound interpretation. GPR55 pharmacology is not fully characterized, and O-1602 may have off-target effects. Translation to human opioid dependence treatment would require extensive further research.

How to read the evidence

This is an animal study testing a relatively novel pharmacological target. While the results are promising, GPR55 research is still in early stages and clinical translation is distant.

When this study was published

Published in 2016. GPR55 research has continued but remains largely preclinical.

The bigger picture

GPR55 is an emerging receptor in cannabinoid pharmacology. This study adds to evidence that the broader endocannabinoid system, beyond just CB1 and CB2 receptors, interacts with opioid pathways. Understanding these interactions could eventually lead to new approaches for treating opioid dependence.

Questions still open

Could GPR55-targeting drugs be developed as treatments for opioid use disorder in humans? Does GPR55 interact with other aspects of the endocannabinoid system that are relevant to addiction?

Common questions

What is GPR55?

GPR55 is a receptor sometimes called the "third cannabinoid receptor" because it responds to some cannabinoid compounds, though it is structurally different from CB1 and CB2 receptors. It is involved in pain modulation and other functions, but its full role is still being characterized.

Could this lead to new treatments for opioid addiction?

The findings suggest GPR55 as a potential pharmacological target, but substantial research would be needed before any clinical application. The current evidence is limited to one mouse study with one compound, and GPR55-targeting drugs for human use have not been developed.

Read the original research

The effect of O-1602, an atypical cannabinoid, on morphine-induced conditioned place preference and physical dependence.

Pharmacological reports : PR, 68(3), 592-7

View on PubMed ↗Publisher’s paper ↗

Citation

Alavi, Mohaddeseh Sadat; Hosseinzadeh, Hossein; Shamsizadeh, Ali; Roohbakhsh, Ali. (2016). The effect of O-1602, an atypical cannabinoid, on morphine-induced conditioned place preference and physical dependence.. Pharmacological reports : PR, 68(3), 592-7. https://doi.org/10.1016/j.pharep.2015.12.009