Influence of afterbirth ingestion on the development of long-term behavioral adaptations that result from repeated exposure to morphine
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Ingestion of placenta or amniotic fluid (AF) (a) facilitates the onset of maternal behavior; (b) enhances pregnancy-mediated analgesia that results from the release of endogenous opioids at parturition; (c) enhances morphine-induced hypoalgesia, even in morphine-tolerant rats; and (d) reduces the effect of abstinence-precipitated withdrawal on pain sensitivity. The latter effects suggest that afterbirth ingestion can modify the expression of morphine-induced adaptations such as tolerance and withdrawal. The present experiments were conducted to investigate whether afterbirth ingestion in conjunction with repeated morphine treatments can also affect the development of morphine-induced adaptations. In Experiment 1, male rats received daily injections of morphine (0, 2, 3, 4 mg/kg, i.p.) in conjunction with AF or saline orogastric infusions for 10 days. Pain threshold was determined in the hot-water tail-withdrawal assay on the day after the last morphine administration to investigate the development of tolerance to the hypoalgesic effects of morphine. Two days after the last morphine administration, pain threshold was assessed again to determine the development of withdrawal symptoms (hyperalgesia); the frequency of wet-dog shakes was observed for three consecutive days. In Experiment 1, repeated exposure to 3 or 4 mg/kg morphine resulted in the development of tolerance to the hypoalgesic effects of 3 mg/kg morphine that was attenuated by AF history. Because the experience of pain threshold testing affected the results of subsequent pain threshold tests it is not clear whether rats developed the withdrawal symptom of hyperalgesia. Morphine History did not modify the frequency of wetdog shakes after cessation of morphine treatment. A history of AF ingestion increased the number of wet-dog shakes on Observation Day 3. In Experiment 2, male rats received daily injections of morphine (0, 2, 5, 10 mg/kg, s.c.) and, at the same time, were allowed to eat placenta or ground-beef control (1 g) for 10 days. Three and 17 days after the last exposure to morphine and placenta, morphine-induced locomotor activity was assessed in an open-field. During these locomotor tests, rats received s.c. injections of morphine every 20 min (0, 1, 2, and then 2 mg/kg, producing cumulative doses of 0, 1, 3, 5 mg/kg), and total locomotor activity after each injection was measured. On Test Day 2 (17 days after the last morphine and placenta treatment), rats with pre-exposure to 5 and 10 mg/kg morphine showed a reduced locomotor response to morphine. Treatments with a combination of placenta and these doses of morphine did not modify the development of this adaptation, probably due to a floor effect. However, a history of placenta ingestion alone (0 mg/kg morphine) or with a concurrent injection of a low dose of morphine (2 mg/kg) also reduced locomotor response to morphine. Therefore, repeated exposure to ingested placenta (either alone or in conjunction with a low repeated dose of morphine), or a high repeated dose of morphine, induced a longterm reduction in the sensitivity to the locomotor-enhancing effects of morphine, thereby facilitating the development of this behavioral adaptation.