Acute naloxone-precipitated morphine withdrawal elicits nausea-like somatic behaviors in rats in a manner suppressed by N-oleoylglycine

Psychopharmacology (Berl). 2020 Feb;237(2):375-384. doi: 10.1007/s00213-019-05373-2. Epub 2019 Nov 11.

Abstract

Rationale: Acute naloxone-precipitated morphine withdrawal (MWD) produces a conditioned place aversion (CPA) in rats even after one or two exposures to high-dose (20 mg/kg, sc) morphine followed 24-h later by naloxone (1 mg/kg, sc). However, the somatic withdrawal reactions produced by acute naloxone-precipitated MWD in rats have not been investigated. A recently discovered fatty acid amide, N-oleoylglycine (OlGly), which has been suggested to act as a fatty acid amide hydrolase (FAAH) inhibitor and as a peroxisome proliferator-activated receptor alpha (PPARα) agonist, was previously shown to interfere with a naloxone-precipitated MWD-induced CPA in rats.

Objectives: The aims of these studies were to examine the somatic withdrawal responses produced by acute naloxone-precipitated MWD and determine whether OlGly can also interfere with these responses.

Results: Here, we report that following two exposures to morphine (20 mg/kg, sc) each followed by naloxone (1 mg/kg, sc) 24 h later, rats display nausea-like somatic reactions of lying flattened on belly, abdominal contractions and diarrhea, and display increased mouthing movements and loss of body weight. OlGly (5 mg/kg, ip) interfered with naloxone-precipitated MWD-induced abdominal contractions, lying on belly, diarrhea and mouthing movements in male Sprague-Dawley rats, by both a cannabinoid 1 (CB1) and a PPARα mechanism of action. Since these withdrawal reactions are symptomatic of nausea, we evaluated the potential of OlGly to interfere with lithium chloride (LiCl)-induced and MWD-induced conditioned gaping in rats, a selective measure of nausea; the suppression of MWD-induced gaping reactions by OlGly was both CB1 and PPARα mediated.

Conclusion: These results suggest that the aversive effects of acute naloxone-precipitated MWD reflect nausea, which is suppressed by OlGly.

Keywords: Acute naloxone-precipitated morphine withdrawal; CB1; Gaping; N-oleoylglycine; Nausea; PPARα; Rats; Somatic MWD.

MeSH terms

  • Animals
  • Female
  • Glycine / analogs & derivatives*
  • Glycine / pharmacology
  • Glycine / therapeutic use
  • Male
  • Medically Unexplained Symptoms
  • Morphine / adverse effects*
  • Morphine Dependence / drug therapy
  • Morphine Dependence / physiopathology
  • Naloxone / toxicity*
  • Narcotic Antagonists / toxicity*
  • Nausea / chemically induced
  • Nausea / drug therapy*
  • Nausea / physiopathology
  • Oleic Acids / pharmacology
  • Oleic Acids / therapeutic use*
  • Rats
  • Rats, Sprague-Dawley
  • Shrews
  • Substance Withdrawal Syndrome / drug therapy*
  • Substance Withdrawal Syndrome / etiology
  • Substance Withdrawal Syndrome / physiopathology

Substances

  • N-oleoylglycine
  • Narcotic Antagonists
  • Oleic Acids
  • Naloxone
  • Morphine
  • Glycine