Morphine-induced supersensitivity to the effects of naloxone on luteinizing hormone secretion in the male rat

The effects of morphine pretreatment on naloxone-induced increases in serum luteinizing hormone (LH) levels were examined in male rats. After a single morphine injection (10 mg/kg), naloxone (0.5 mg/kg)-induced increases in serum LH levels were initially suppressed (0-3 hr), but returned to normal by 4 hr. Five to 24 hr after morphine pretreatment, however, naloxone-precipitated increases in LH were markedly exaggerated with the peak effect occurring at 6 hr (4 times greater than saline-pretreated controls). In morphine-implanted rats (75-mg lellet, 48 hr earlier), the enhanced sensitivity to naloxone was considerably more dramatic than that found after acute administration. Naloxone-induced increases in serum LH levels were more than 40 to 50 times greater in morphine-implanted animals than they were in placebo-implanted rats at the respective ED₅₀ dose. Naloxone dose-response curves revealed that the naloxone ED₅₀ was reduced by either morphine pretreatment regimen, but was much more pronounced in pellet-implanted animals [181.6 μg/kg in controls; 116.4 μg/kg in acutely morphinized animals P < .05); and 4.39 μg/kg in morphine-implanted rats (P < .001)]. The only distinction between acute and chronic morphine administration was in the magnitude of the shift in the naloxone ED₅₀ as identical peak increases in LH were obtained in both groups. Finally, our data indicate that naloxone-induced increases in serum LH levels can serve as a useful and sensitive means to assess opiate dependence. The mechanisms underlying the morphine-induced enhancement of the effects of naloxone on serum LH levels are not fully understood, but we found no differences in the uptake of naloxone into brain as a function of morphine pretreatment.