The Cannabinoid Receptor Type 1 Positive Allosteric Modulator ZCZ011 Attenuates Naloxone-Precipitated Diarrhea and Weight Loss in Oxycodone-Dependent Mice

J Pharmacol Exp Ther. 2022 Jan;380(1):1-14. doi: 10.1124/jpet.121.000723. Epub 2021 Oct 8.


Opioid use disorder reflects a major public health crisis of morbidity and mortality in which opioid withdrawal often contributes to continued use. However, current medications that treat opioid withdrawal symptoms are limited by their abuse liability or lack of efficacy. Although cannabinoid 1 (CB1) receptor agonists, including Δ9-tetrahydrocannabinol, ameliorate opioid withdrawal in both clinical and preclinical studies of opioid dependence, this strategy elicits cannabimimetic side effects as well as tolerance and dependence after repeated administration. Alternatively, CB1 receptor positive allosteric modulators (PAMs) enhance CB1 receptor signaling and show efficacy in rodent models of pain and cannabinoid dependence but lack cannabimimetic side effects. We hypothesize that the CB1 receptor PAM ZCZ011 attenuates naloxone-precipitated withdrawal signs in opioid-dependent mice. Accordingly, male and female mice given an escalating dosing regimen of oxycodone, a widely prescribed opioid, and challenged with naloxone displayed withdrawal signs that included diarrhea, weight loss, jumping, paw flutters, and head shakes. ZCZ011 fully attenuated naloxone-precipitated withdrawal-induced diarrhea and weight loss and reduced paw flutters by approximately half, but its effects on head shakes were unreliable, and it did not affect jumping behavior. The antidiarrheal and anti-weight loss effects of ZCZ0111 were reversed by a CB1 not a cannabinoid receptor type 2 receptor antagonist and were absent in CB1 (-/-) mice, suggesting a necessary role of CB1 receptors. Collectively, these results indicate that ZCZ011 completely blocked naloxone-precipitated diarrhea and weight loss in oxycodone-dependent mice and suggest that CB1 receptor PAMs may offer a novel strategy to treat opioid dependence. SIGNIFICANCE STATEMENT: Opioid use disorder represents a serious public health crisis in which current medications used to treat withdrawal symptoms are limited by abuse liability and side effects. The CB1 receptor positive allosteric modulator (PAM) ZCZ011, which lacks overt cannabimimetic behavioral effects, ameliorated naloxone-precipitated withdrawal signs through a CB1 receptor mechanism of action in a mouse model of oxycodone dependence. These results suggest that CB1 receptor PAMs may represent a viable strategy to treat opioid withdrawal.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation
  • Animals
  • Antidiarrheals / therapeutic use*
  • Cannabinoid Receptor Agonists / therapeutic use*
  • Diarrhea / drug therapy*
  • Diarrhea / etiology
  • Female
  • Indoles / therapeutic use*
  • Male
  • Mice
  • Mice, Inbred ICR
  • Naloxone / adverse effects
  • Narcotic Antagonists / adverse effects
  • Narcotics / toxicity
  • Opioid-Related Disorders / drug therapy
  • Opioid-Related Disorders / etiology
  • Oxycodone / toxicity
  • Receptor, Cannabinoid, CB1 / metabolism
  • Substance Withdrawal Syndrome / drug therapy*
  • Substance Withdrawal Syndrome / etiology
  • Thiophenes / therapeutic use*


  • 6-methyl-3-(2-nitro-1-(thiophen-2-yl)propyl)-2-phenyl-1H-indole
  • Antidiarrheals
  • Cannabinoid Receptor Agonists
  • Indoles
  • Narcotic Antagonists
  • Narcotics
  • Receptor, Cannabinoid, CB1
  • Thiophenes
  • Naloxone
  • Oxycodone