Brain β-Endorphin Immunoreactivity as an Index of Cocaine and Combined Cocaine–Ethanol Toxicities

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The present study examines alterations in the cytoplasmic immunoreactivity of brain β-endorphin, an endogenous opioid peptide regarded as the mediator of both euphoria and antinociceptive systems, in relation to toxicities due to cocaine and combined cocaine–ethanol. β-endorphin–immunoreactive cells were visualized and counted in adjacent sections from male rat brains at the level of the arcuate nucleus. In this region, cytoplasmic β-endorphin immunoreactivity is prevalent. An intraperitoneal injection of cocaine (75 or 15 mg/kg) was given 15 min after an intraperitoneal injection of 3 g/kg ethanol or vehicle. With a fatally toxic dose (75 mg/kg) of cocaine, the number of neurons exhibiting cytoplasmic β-endorphin immunoreactivity (immunoreactive nerve cells) was significantly increased immediately after the drug administration. Ethanol further enhanced the effects of both 15 and 75 mg/kg of cocaine. When the immunoreactivity was visually estimated by computer imaging analysis, lightly stained, weakly immunoreactive cells with photographic light absorption values greater than 50% were enhanced in the cocaine–ethanol groups compared to the cocaine only groups. Fatal toxicities were only observed in the groups treated with the high cocaine doses (75 mg/kg), with or without ethanol. In these groups, the number of strongly immunoreactive cells had increased significantly compared to the other groups. In the group treated with the high cocaine dose (75 mg/kg) plus ethanol, an increased frequency of late deaths that occurred over 1 h after the drug administration was observed, together with a decreased severity of cocaine-induced seizures and an early enhancement of weakly immunoreactive cells. Unlike the strongly immunoreactive cells, the weakly immunoreactive cells appeared to be continuously enhanced, based on an experiment examining β-endorphin immunoreactivity at 24 h after an injection of 50 mg/kg cocaine.