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 pellet, 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 micrograms/kg in controls; 116.4 micrograms/kg in acutely morphinized animals (P less than .05); and 4.39 micrograms/kg in morphine-implanted rats (P less than .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.