Effect of pretreatment with pertussis toxin on the development of physical dependence on morphine.

The effect of intracerebroventricular (i.c.v.) pretreatment with pertussis toxin (PTX) on the development of physical dependence on morphine was investigated in mice. Twenty four hours after PTX (0.5 microgram, i.c.v.) or vehicle pretreatment, the mice were chronically treated with morphine (8-45 mg/kg, s.c.) for 5 days. Several withdrawal signs were observed following naloxone challenge in morphine-dependent mice which had been pretreated with vehicle. In addition, 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) and noradrenaline (NA) turnover (MHPG/NA) levels in the cerebral cortex were increased following naloxone challenge in morphine-dependent mice. These findings indicate that activation of the central noradrenergic system may mediate the expression of some withdrawal signs. In contrast, pretreatment with PTX attenuated the naloxone-precipitated withdrawal signs in morphine-dependent mice. The incidence of withdrawal signs such as jumping, "wet dog" shakes, and rearing was significantly reduced by PTX pretreatment. PTX pretreatment also prevented the naloxone-precipitated increases in MHPG concentration and NA ratio (MHPG/NA) in the cerebral cortex, suggesting that central PTX-sensitive GTP-binding proteins (G-proteins) may be involved in the elevation of NA transmission in the cortex which projects from the locus coeruleus (LC) during morphine withdrawal. The blocking effects of PTX on the behavioral and biochemical changes after withdrawal suggest that central PTX-sensitive G-proteins (Gi/Go) may play an important role in the development of physical dependence on morphine.