Prior experience of morphine application alters the c-fos response to MDMA ('ecstasy') and cocaine in the rat striatum.

Repeated morphine application usually leads to the development of tolerance but under certain circumstances sensitization may arise simultaneously. This phenomenon becomes obvious in behavioral tests as increasing locomotor activity and increasing drug self-administration during a course of chronic morphine application. It was suggested recently that sensitization could contribute to addiction. The molecular mechanisms of sensitization may include the long lasting increase in neuronal responsiveness to morphine which was observed in defined brain areas after repeated morphine injections. In this work, we studied whether morphine-sensitized Wistar rats also display an enhanced neuronal activity in response to other drugs of abuse (so called co-sensitization). The substances to be tested were injected as single doses 4 weeks after completion of a 10-day morphine pretreatment. MDMA (3, 4-methylenedioxymethamphetamine, 6 mg/kg) as a single test dose yielded a c-fos response in a wide range of brain areas. In the caudate putamen, the expression pattern of c-fos was clearly altered if the rats had received repeated morphine application previously. In this case, the MDMA-induced c-fos expression was markedly confined to the centromedial, mesolimbic aspect of the striatum whereas it had a diffuse appearance in rats not exposed to the opiate earlier. Cocaine application (50 mg/kg) elicited an intense c-fos expression in the medial striatum if the animals were morphine-pretreated; it was virtually absent in drug-naive rats after the same cocaine dose. Ten mg/kg cocaine had a similar but weaker effect. No difference in the c-fos expression pattern between morphine and saline pretreated animals was observed in the case of a THC (Delta(9)-tetrahydrocannabinol, 25 mg/kg) or an LSD (lysergic acid diethylamide, 1 mg/kg) test application. These findings imply that morphine sensitizes the brain towards other addicting drugs. In consequence, morphine sensitization obviously does not solely reflect alterations in mu-opioid receptor signaling. Rather, it seems to reflect further rearrangements within the mesolimbic system.