Administration of morphine to outbred female rats is shown to result in increased anxiety in the conflict test and reduced pain sensitivity in the tail flick test in 2.5-monthold offspring. In prenatally morphinized offspring the analgetic effect of morphine was enhanced, while the anxiolytic effect of buspirone was lower than in intact animals, which suggests rearrangements in the opioid and serotoninergic systems of the brain.Key Words: morphine; offspring; anxiety Narcotics abuse is becoming more and more widespread. Of particular concern is the growing addiction among women in many countries [2,8,11]. Numerous investigations have established adverse effects of narcotics on pregnancy and fetal development. The majority of authorities report the withdrawal syndrome in newborns [4,6,10,15] and high prenatal mortality [12], as well as various congenital abnormalities [6,9]. However, the longterm consequences of the prenatal effect of narcotics on the fetus are still poorly understood.The aim of our study was to investigate the anxiogenic behavior and pain sensitivity of rats exposed to morphine in utero. MATERIALS AND METHODSThe experiments were performed on outbred male rats, whose mothers had received intraperitoneal injections of morphine (10 mg/kg, twice a day) from the 9th to 19th day of gestation. The mothers of control rats were injected with isotonic NaC1 solution during the same period. The 2.5-, 4-, and 5-month-old rat pups were tested in a conflict situation as described earlier [14] with modifications [3]. In brief, after a 48-hour water deprivation the animals were daily during 2 days placed for 10 rain in a setup where they were allowed to drink water from a dish. On the third day, 10 sec after the first water intake an electrical current (0.5 mA) was applied to the setup and the number of punishable water intakes, accompanied by shocking, was automatically recorded. In 2.5-month-old animals conflict behavior was also recorded against the background of phenazepam (1 mg/kg) and buspirone (5 mg/kg) injected intraperitoneally 30 rnin before the test. The pain sensitivity of 2.5-and 4-month-old rats was assessed in the taft flick test by measuring the latency of taft withdrawal in response to thermal stimulation. The analgetic effect of morphine (5 mg/kg, i.p. 30 rain before the experiment) was studied in 2.5-month-old rats using the same test. The statistical processing of the results was performed using the Student t test [5].
It is established that mature random-bred and Wistar rats exhibit the same level of pain sensitivity in the tail-flick test, but the analgetic effect of morphine (5 mg/kg) is variously expressed: marked hypalgesia is observed in mongrel but not in Wistar rats. Prenatal morphinization enhances the analgetic effect of morphine in both mongrel and Wistar rats. There is a direct correlation between the plasma morphine content in prenatally morphinized rats and their sensitivity to the analgetic action of morphine.Key Words: morphine; prenatal period; offspring; pain sensitivity A reduced pain sensitivity has been demonstrated in offspring of random-bred female rats injected with morphine during pregnancy [1,5]. This effect may be attributed to both a reduced number of opioid receptors [10] and disturbed morphine pharmacokinetics in the brain. However, the changes in the pharmacokinetics of morphine in prenatally morphinized offspring remain poorly understood. It is possible that morphine, which readily crosses the placental barrier [2,3] and enters the developing fetus, is able to modify the activity of enzyme systems involved in opiate metabolism in children and adults. The aim of the present study was, first, to elucidate whether pharmacokinetic mechanisms govern the changes observed in prenatally morphinized rats and, second, to compare the nociceptive reaction in genetically different Wistar and mongrel rats. MATERIALS AND METHODSThe experiments were carded out in male Wistar and mongrel rats, whose mothers were injected with morphine in a dose of 10 mg/kg every 12 hours from the 9th to the 19th day of gestation. The mothers of controls were injected with the same volume of 0.9% NaC1 at the same times of gestation. The nociceptive reaction was evaluated in the tail-flick test by the latency of tail withdrawal in response to a thermal stimulus. After determination of the background pain sensitivity, 2.5-month-old offspring were intraperitoneally injected with morphine hydrochloride in a dose of 5 mg/kg and the latency of the pain reaction was redetermined. In male Wistar pups the background pain sensitivity was also determined at the age of one month. In 12 Wistar rats (6 experimental animals and 6 controls) the plasma concentration of morphine 10 min after intraperitoneal injection in a dose of 20 mg/kg was measured by high performance liquid chromatography [9] in our modification. The results were processed statistically using the Student t test. RESULTSA reliably decreased pain sensitivity was observed in prenatally morphinized mongrel 2.5-month-old mongrel rats. Morphine injection increased the latency of the noeiceptive reaction more than 2-fold in mongrel rats, both prenatally morphinized and controis. However, the latency in prenatally morphinized 0007-4888/95/0009-0913512.50 9Plenum Publishing Corporation
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