GHB ameliorates naloxone-induced conditioned place aversion and physical aspects of morphine withdrawal in mice

Rationale Gamma-hydroxybutyric acid (GHB) is a naturally occurring substance in the brain, the administration of which has proved useful in the treatment of the opiate withdrawal symptoms in humans.Objectives The aim of the present work was to validate this beneficial effect on the physical and motivational aspects of morphine withdrawal in mice.Methods In a first experiment, animals rendered morphine-dependent were conditioned to develop a place aversion (CPA) to the compartment paired with naloxone administration in a two-chamber apparatus. The conditioning phase consisted of three pairings of either naloxone (0.250 mg/kg) or vehicle in one compartment, both with similar time allotments during the preconditioning test. During the testing phase, mice were again allowed to explore the entire apparatus. GHB (6, 12.5, 25, and 50 mg/kg) was administered during either the acquisition or expression phase of this conditioning. In a second experiment, the capacity of GHB to ameliorate the intensity of physical signs of morphine withdrawal was evaluated.Results GHB blocked CPA in both phases: administered during acquisition (from 12.5 mg/kg and higher) as well as in the expression phase (from 6 mg/kg, except for 25 mg/kg). It also decreased the intensity of physical signs of morphine withdrawal to near control levels measured by the modified Gellert–Holtzman scale (25 mg/kg and higher). Decreases in jumping, body shakes, and paw tremor were also observed.Conclusions Our results support the idea that GHB ameliorates both aspects of morphine withdrawal, physical as well as motivational signs.