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

Abstract

In vitro and in vivo studies have shown that abused solvents affect different neurotransmitter systems, including the GABAergic, glutamatergic, and opioidergic. The first purpose of this study was to determine in mice whether an acute exposure to 4,000 ppm toluene or 12,000 ppm 1,1,1-trichloroethane (TCE) modifies receptor binding levels to: (a) DAMGO, a mu-opioid receptor selective agonist; (b) MK-801, a noncompetitive selective NMDA-receptor antagonist; and (c) flunitrazepam, a benzodiazepine binding site selective agonist. In addition, in separate groups of animals, nociceptive effects of toluene alone or co-administered with morphine were evaluated in the hot-plate test. Mice were exposed to toluene or TCE in static exposure chambers for 30 min, and their brains were removed 24 h later for autoradiography. Acute toluene inhalation produced a significant decrease in mu-opioid receptor binding levels in cingulate and piriform cortices, caudate putamen, thalamus, amygdala, and periaqueductal gray, whereas TCE significantly decreased mu-opioid receptor levels, but only in thalamus and periaqueductal gray. Both toluene and TCE decreased benzodiazepine receptor binding levels in discrete brain areas, but had no effect on NMDA receptor levels. In the hot-plate test, a single toluene exposure counteracted morphine antinociceptive response when the solvent exposure time was immediately followed by morphine treatment, but not when morphine was administered 24, 48, 72, and 96 h later. However, co-administration of morphine and toluene 24, 48, 72, and 96 h after the single solvent exposure resulted in morphine-induced analgesia blockade. Present results suggest that mu-opioid receptors are an important molecular target for organic solvents, and that the inhalation of these compounds may affect the analgesic properties of opioids.

Negative allosteric modulation of GABAA receptors inhibits facilitation of brain stimulation reward by drugs of abuse in C57BL6/J mice

“…However, a dose of flumazenil sufficient to block a high efficacy benzodiazepine-site agonist had no effect on ICSS facilitation produced by either methamphetamine or toluene. These data are consistent with flumazenil's clinical profile as a BDZ antagonist (Votey et al 1991) and supports previous literature demonstrating that neither toluene nor methamphetamine interact directly with the BDZ binding site of GABA A receptors (Páez-Martínez et al 2008). In contrast, Ro15-4513 completely blocked d-methamphetamine, toluene and diazepam- facilitated ICSS.…”

Pharmacological Characterization of the Discriminative Stimulus of Inhaled 1,1,1-Trichloroethane

“…For instance, acute exposure to 12,000 ppm TCE significantly decreased -opioid receptor binding in mice examined 24 h after exposure (Paez-Martinez et al, 2008). Trichloroethylene suppression of sexual behavior in male rats is blocked by naltrexone (Nelson and Zenick, 1986), and trichloroethylene anesthesia reduced the need for postoperative analgesia compared with other inhaled anesthetics (Rice and Reynolds, 1987).…”

“…Perchloroethylene inhibits nicotinic acetylcholine receptors expressed in oocytes (Bale et al, 2005) and voltage-sensitive Ca 2ϩ channels in pheochromocytoma cells . Chlorinated hydrocarbons have also been shown to have effects that may result from actions at opioid receptors (Nelson and Zenick, 1986;Paez-Martinez et al, 2008). Which, if any, of these receptor systems are responsible for the abuse-related behavioral effects of these compounds is unclear.…”

Chronic and intermittent morphine treatment differently regulates opioid and dopamine systems: a role in locomotor sensitization

“…For D2 receptors, sections were preincubated in 50 mM Tris-HCl buffer (pH 7.4) supplemented with 120 mM NaCl and 5 mM KCl for 30 min at 25°C and then incubated in the same buffer containing 2 nM [ 3 H]-raclopride (Perkin Elmer, France), in the absence (total binding) or presence (nonspecific binding) of 10 μM 2-bromo-alpha-ergocryptine (Sigma-Aldrich, France) for 60 min at 25°C (Tien et al 2003). For mu opioid receptors, brain sections were preincubated in 50 mM Tris-HCl (pH 7.4) for 30 min at 25°C and then incubated for 60 min at 25°C in the same buffer containing 2 nM [ 3 H]-D-Ala2,N-MePhe4,Gly-ol5-enkephalin ([ 3 H]-DAMGO, Perkin Elmer, France) in the presence (nonspecific binding) or absence (total binding) of 10 μM naloxone (Sigma-Aldrich, France) (Paez-Martinez et al 2008). It is noteworthy that chronic or intermittent morphine treatment did not modify the K d of [ 3 H]-SCH23390, [ 3 H]-raclopride, or [ 3 H]-DAMGO measured on brain membranes (T Le Marec, F Noble, N Marie; unpublished results).…”