CB 1 positive allosteric modulation attenuates Δ 9-THC withdrawal and NSAID-induced gastric inflammation

Pharmacol Biochem Behav. 2019 Feb;177:27-33. doi: 10.1016/j.pbb.2018.12.009. Epub 2018 Dec 28.

Abstract

Recently, multiple compounds have been synthesized that target the allosteric binding site(s) of CB1. These CB1 positive allosteric modulators may capture the benefits of cannabinoid receptor activation without unwanted psychoactive effects, such as sedation. For example, ZCZ011 blocks neuropathic pain, absent the catalepsy, sedation, and hypothermia caused by CB1 orthosteric modulators, including Δ9-tetrahydrocannabinol (THC). The primary goal of the present study was to evaluate the potential of ZCZ011 to attenuate somatic signs of cannabinoid withdrawal in mice. Mice were repeatedly administered THC (10 mg/kg, s.c.) or vehicle, and withdrawal was either precipitated using the CB1 antagonist rimonabant (3 mg/kg, i.p.) or elicited spontaneously via THC abstinence. ZCZ011 (≥10 mg/kg, i.p.) significantly attenuated somatic signs of withdrawal, including head twitches and paw tremors, but had no effect on locomotor activity or conditioned place preference. We next tested the antiulcerogenic properties of CB1 positive allosteric modulation. Mice were fasted for 22 h, administered ZCZ011, and gastric hemorrhages were induced with the nonsteroidal anti-inflammatory drug diclofenac sodium (100 mg/kg, p.o.). ZCZ011 alone had no effect on gastric ulceration, but ZCZ011 (≥10 mg/kg) blocked ulcer formation when combined with a subthreshold MAGL inhibitor (JZL184; 1 mg/kg, i.p.). Thus, CB1 positive allosteric modulation is a novel approach to treat cannabinoid dependence and gastric inflammation.

Keywords: CB1 allosteric modulation; Cannabinoid dependence; Cannabis use disorder; Drug abuse; NSAID induced gastritis.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Allosteric Regulation
  • Allosteric Site
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / administration & dosage
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Benzodioxoles / pharmacology
  • Benzodioxoles / therapeutic use*
  • Cannabinoid Receptor Agonists / administration & dosage
  • Cannabinoid Receptor Agonists / pharmacology*
  • Diclofenac / administration & dosage
  • Diclofenac / pharmacology*
  • Dronabinol / administration & dosage
  • Dronabinol / pharmacology*
  • Drug Therapy, Combination
  • Gastritis / chemically induced*
  • Gastritis / drug therapy*
  • Indoles / pharmacology
  • Indoles / therapeutic use*
  • Locomotion / drug effects
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred ICR
  • Monoacylglycerol Lipases / antagonists & inhibitors
  • Peptic Ulcer Hemorrhage / chemically induced
  • Peptic Ulcer Hemorrhage / drug therapy
  • Piperidines / pharmacology
  • Piperidines / therapeutic use*
  • Receptor, Cannabinoid, CB1 / antagonists & inhibitors
  • Receptor, Cannabinoid, CB1 / metabolism*
  • Rimonabant / pharmacology
  • Stomach Ulcer / chemically induced
  • Stomach Ulcer / drug therapy
  • Substance Withdrawal Syndrome / drug therapy*
  • Thiophenes / pharmacology
  • Thiophenes / therapeutic use*

Substances

  • 6-methyl-3-(2-nitro-1-(thiophen-2-yl)propyl)-2-phenyl-1H-indole
  • Anti-Inflammatory Agents, Non-Steroidal
  • Benzodioxoles
  • Cannabinoid Receptor Agonists
  • Indoles
  • JZL 184
  • Piperidines
  • Receptor, Cannabinoid, CB1
  • Thiophenes
  • Diclofenac
  • Dronabinol
  • Monoacylglycerol Lipases
  • Rimonabant