Toluene Alters Mu-Opioid Receptor Expression in the Rat Brainstem.

Abstract

Toluene is an ototoxic organic solvent widely used in industry and could be a cause of sleep apnea. Acute toluene administration in rats induces an increase in the number of neural cells immunostained for mu-opioid receptors in several brainstem nuclei, such as the inferior colliculus, dorsal and lateral periaqueductal gray and dorsal raphe, without changes in the superior colliculus and the interpeduncular and lateral reticular nuclei. These data suggest that mu-opioid receptors could be involved in toluene-induced neurotoxic effects on the physiological regulation of breathing during sleep, and auditive function. Key words: Toluene, Mu-opioid receptors, Rat brain Materials and MethodsThe experimental animals were carefully handled and all experiments were carried out in accordance with the law, avoiding animal suffering. Toluene with purity of 99% (Analytical reagent grade, Quimon Chem. Co., Spain) was used. Toluene was diluted with olive oil at a concentration of 1 ml/ml and administered intraperitoneally to the experimental group (n=6) at a dose of 1.3 ml/kg/day for 5 consecutive days. The selected dose was 1/2 of the LD 50 per day. This dose and this kind of administration have been employed to carry out studies on the adverse effects of organic solvents 15) . The LD 50 in rats has been found in our laboratory to be 2.61 ± 0.41 ml/kg/day, calculated by the Bliss method. The control group (n=6) was given 0.9% NaCl solution in the same volume and duration as the experimental group. Two hours after the last treatment, the animals were anaesthetized with Equithensin (2 ml/kg), an alcoholic solution of nembutal and chloral hydrate (Sigma-Aldrich Química S. A.), intraperitoneally and perfused transcardially under deep anaesthesia with saline plus 50 mM phosphate buffer, pH 7.4, followed by 4% paraformaldehyde (Sigma-Aldrich Química S. A.). The brains were removed, cut into smaller pieces and then immersed in the same fixative medium overnight. They were stored for 2 days in 0.1 M phosphate buffer containing

Toluene and TCE Decrease Binding to Mu‐Opioid Receptors, but Not to Benzodiazepine and NMDA Receptors in Mouse Brain

“…According to von Euler and coworkers, 16 exposure to 80 ppm toluene 6 h/day, 5 days/week for 3 months produced an increase in mu‐opioid receptor levels in nucleus accumbens (27%), but not in caudate putamen or frontoparietal‐insular cortex in rats. In another study, Saracibar and coworkers 17 demonstrated that i.p. administration of 0.56 mg/kg toluene, once a day for 5 days, increased mu‐opioid receptor immunostaining in raphe dorsal nuclei, inferior and superior colliculus, and periaqueductal gray of rats.…”

“…At the molecular level, several studies have found that, similarly to ethanol, 10–12 solvents potentiate GABA A receptor function 13 and act as noncompetitive NMDA receptor antagonists, among other actions 14,15 . Additionally, in vitro studies have shown that repeated solvent exposure produces changes in mu‐opioid receptor levels in diverse brain areas 16,17 . On the other hand, behavioral studies have reported that toluene and TCE increase locomotor behavior, impair motor coordination, 18 have anxiolytic‐like actions, 18,19 and increase nociception 19,20 …”

Inhalant abuse among adolescents: neurobiological considerations

“…toluene for 6 h a day, 5 days a week over 3 months resulted in reduced [ 3 H]neurotensin binding in the orbital cortex, but increased accumbal binding of [ 3 H]etorphine to opioid receptors ( von Euler et al ., 1988 ). More recently, acute toluene exposure was shown to increase μ‐opioid receptor protein in brain stem nuclei, including the dorsal raphe and periaqueductal grey ( Saracibar et al ., 2001 ), whereas seven daily injections of toluene (600 mg kg −1 i.p.) increased dopamine and serotonin levels in rat basal ganglia ( Riegel et al ., 2004 ).…”

Relationship of opioid receptors with GABAergic neurons in the rat inferior colliculus

“…In rats, acute administration of toluene, a solvent with ototoxic properties, induces an increase in the number of neural cells immunostained for MOR in several brainstem nuclei including the IC. These data have been interpreted to indicate a link between opioid receptors and auditory function (Saracibar et al ., 2001).…”