On PD 42 ANOVA analysis of the open field activity revealed significance [F(3,32)=10.2, P<0.001]; however, the post-hoc test showed sex, but no exposure difference. There were neither exposure nor sex differences in locomotor activity during habituation at PD 42. The results show that habituation to novel surroundings was slower in perinatally MO exposed pups 2 days after weaning (data not shown).
There was no difference in the open field locomotor activity of pups exposed to SAL-(group II/3, s/s), to MO postnatally (group II/4, s/m) or to MO prenatally (group II/5, m/s) [F(5,44)=1.04] on PD 23 (Fig. 1, panel b). In the subsequent 30 min (habituation) the locomotor activity of both the postnatally MO-exposed (group II/4, s/m) and the prenatally MO-exposed (group II/5, m/s) male pups was significantly higher than that of the SAL-exposed (group II/3, s/s) ones [F(1,54)=8.96, P<0.01 and F(1,39)=19.96, P<0.001, respectively]. The locomotor activity of male pups exposed to MO during gestation (group II/5, m/s) was significantly higher [F(1,45)=4.17, P<0.05] than those exposed to MO during lactation (group II/4, s/m). The results show that habituation of both MO-exposed male groups was slower; the difference was more marked in the case of prenatal exposure. There was no difference in the habituation between the female groups (Fig. 2, panel b).
Sensitivity of MO-exposed male offspring (group I/2, m/m) to the antinociceptive effect of MO was lower on PD 24 (3 days after weaning) than that of the SAL-exposed ones (group I/1, s/s) and a moderate decrease of sensitivity was observable in the group of MO-exposed females, too. 95% CL values depicted in Table 3 show no overlap in the case of males. As another approach, a test dose of MO causing an MPE of approximately 50% was selected. This common dose was 3 mg/kg. Applying one-way ANOVA to the data sets of MPEs obtained with this dose, a significant difference [F(3,16)=4.95, P<0.05] was shown; Newman–Keuls post-hoc test indicated a P value of 0.05 for males.
The tendency of difference was observed even on PD 90 in males; however, the difference was already not statistically significant. In the case of females, the moderate decrease absolutely disappeared by PD 90 (Fig. 3). ED50 (95% CL) values are shown in Table 3.
There was no difference in sensitivity to the antinociceptive effect of MO among the offspring exposed to SAL (group II/3, s/s), exposed to MO postnatally (group II/4, s/m) or prenatally (group II/5, m/s), checked on PD 24. However, the prenatally MO-exposed females showed a moderate, albeit not significant reduction (Fig. 4).
Conditioned place preference
MO (1 and 3 mg/kg) failed to induce CPP in SAL-exposed (group I/1, s/s) males; however, it induced a moderate place preference in MO exposed (group I/2, m/m) animals. The difference was statistically significant [F(3,28)=11.70, P<0.001]. Sensitivity of females to the CCP-inducing effect of MO was more marked both in SAL and MO-exposed groups than that of males. In females the difference between the SAL-exposed (group I/1, s/s) and the MO-exposed (group I/2, m/m) animals was highly significant [F(3,28)=49.01, P<0.001]. The Newman–Keuls post-hoc test showed significant exposure differences for both challenge doses of MO (Fig. 5, panel a).
Animals exposed to MO during gestation (group II/5, m/s) displayed significantly higher place preference after MO conditioning (3 mg/kg) than animals exposed to MO during lactation (group II/4, s/m) (t=5.86 for males and 12.06 for females (d.f.=14) P<0.001 in both cases; Fig. 5, panel b).
The aim of the present experiments was to differentiate the behavioural consequences of peri, pre and postnatal MO exposure in rats. As far as we know this is the first comprehensive long-term behavioural study on the consequences of a complete perinatal MO exposure.
In preliminary studies (not shown) a starting dose of 5 mg/kg MO twice a day was used and the dose was increased gradually. The maximal dose (30 mg/kg twice daily) was reached on the 5th day, and then this dose was continued. Although all the dams survived throughout the experiment, there was no normal parturition in the group of MO-treated dams and abortion, premature delivery and death of pups after birth were observed. The average size of litters was less than one. Siddiqui et al. (1997) managed a long MO treatment before and during pregnancy with relatively high doses (the maximal dose during gestation was 30 mg/kg/day) and reported that only 43% of MO-treated dams became pregnant and the number of still-births was significantly higher. That is why in the present series of experiments a constant medium dose of MO (10 mg/kg) was applied once a day. This schedule did not result in differences in the weight gain of dams, the size of litters, or in pup mortality, indicating that the dose of MO did not influence the physical state of dams.
Prenatal MO-exposure significantly decreased the birth weight of offspring measured on PD 1. Similar results have been published following prenatal methadone exposure (Kunko et al., 1996), while Slamberova et al. (2005) and Gagin et al. (1997), did not observe reduced birth weight as a consequence of MO exposure. In their experiments, however, shorter period of MO exposure and other strains (Sprague--Dawley and Fischer 344, respectively) were applied.
The weight gain of pups varied according to the period of MO exposure. When the animals were exposed to MO during the whole perinatal period (experiment I) their weight gain was significantly higher than that of the SAL-exposed peers. The decreased birth weight of MO exposed offspring observed by us at the beginning and followed by a weight gain similar to control peers, are in good correlation with human data. Birth weight of human babies born with neonatal abstinence syndrome was significantly lower compared to control ones, while no difference was shown at the age of 18 months (Hunt et al., 2008). In contrast to our results Siddiqui et al. (1997) found significant slowness in weight gain until PD 60, following a much more marked MO exposure.
In contrast to complete perinatal MO exposure (experiment I), both withdrawal of MO after parturition or starting the MO exposure after parturition only resulted in lower weight gain (experiment II). Why MO-exposure through maternal milk resulted in reduced weight gain in animals exposed only postnatally (experiment II), while just the opposite, higher weight gain was observed in pups exposed already prenatally (experiment I) remains to be elucidated. One possible explanation may be that prenatally MO-exposed pups were already tolerant to the anorexigenic effect of MO. This is supported by the results, that decreased sensitivity to the antinociceptive action of MO in the tail-flick test was also shown.
We can also presume that administration of MO to MO-naïve dams until parturition disturbed the maternal behaviour and/or lactation, while it failed to influence these behavioural patterns in the dams already treated with MO during gestation. Our results that withdrawal of MO after parturition also reduced the weight gain of pups support the role of disturbed maternal behaviour. In this case, however, we cannot exclude the direct effect of MO withdrawal on pups.
In our experiments the complete perinatal MO exposure (experiment I) resulted in delayed habituation to a new environment, decreased sensitivity to the antinociceptive effects of MO and enhanced sensitivity to the reinforcing effect of MO. Sex differences in these behavioural tests were also observed.
The development of tolerance to the antinociceptive effect of MO in newborn rats has been reported earlier. In the majority of these reports, however, the pups were treated with twice-daily high dose (20 mg/kg) MO (Van Praag and Frenk, 1991; Barr andt Wang, 1992), or opioids were administered by infusion (Thornton and Smith, 1997; Thornton et al., 1997). Reduced analgesic response to MO challenge was found in 4-day-old pups exposed perinatally to methadone or buprenorphine through maternally implanted osmotic minipumps (Robinson and Wallace, 2001), or on PD 14 in offspring whose mother was treated s.c. with MO during gestation and lactation (Chiou et al., 2003). None of these papers reported sex differences.
It is necessary to emphasize that, in contrast to the above cited papers, we measured decreased sensitivity to the antinociceptive action of MO 3 days after weaning (i.e. 3 days after cessation of MO exposure) and found this to be significant only in males. In addition, more than 2 months after cessation of MO exposure (PD 90) a tendency to respond only to higher doses of MO was still detectable.
A large body of literature shows sex differences in the sensitivity to the acute effects of opioids in sexually mature adult rats. Males were more sensitive to the antinociceptive action (Cicero et al., 1997; Craft et al., 1999), or to the locomotor suppressant effect of MO (Craft et al., 2006). Both MO-naïve and MO-tolerant neonatal rats, however, were reported to respond sex-independently to the antinociceptive effect of MO or fentanyl (Thornton and Smith, 1997; Thornton et al., 1997) and no sex difference in the reduced analgesic response was observed in 20-day-old rats treated daily with 3 mg/kg MO from PD 1 until PD 9 (Zhang and Sweitzer, 2008). In contrast to these results, we observed a greater decrease in the analgesic effect of MO in males 3 days after weaning; the differences in the results can be explained by the different postnatal ages and/or the different methods to develop tolerance.
The delayed habituation to the new environment measured 2 days after weaning was also more marked in males in our experiments. Our results are in contrast to some recent data which indicate that opioid-naïve periadolescent (PD 29) males are less active in a novel environment than females (White et al., 2008). It is important to emphasize, however, that we observed the delayed extinction of investigatory behaviour in perinatally MO-exposed rats.
However, the role of withdrawal 2 days after weaning must be taken into consideration, and the sex differences found in habituation might be related to this factor. MO-dependent males show higher sensitivity than females to naloxone precipitated withdrawal (Craft et al., 1999). Although naloxone decreases locomotor activity in adult MO-dependent rats, which is considered as a sign of withdrawal (Schulteis et al., 1994; Timár et al., 2005), in neonatal MO-dependent rats naloxone enhanced locomotor activity (Thornton et al., 1997; Stoller et al., 2002). If the delayed habituation that we observed can be considered as a moderate spontaneous withdrawal symptom, the more marked withdrawal in males may explain the slower habituation. The role of withdrawal in delayed habituation is supported by the result that three weeks later, in late adolescence (PD 42) no deficit in habituation was shown. This hypothesis, however, cannot explain the results of experiment II, where higher delay in habituation was observed in animals exposed to MO during gestation than during lactation.
In the present experiments the place preference-inducing effect of MO significantly increased in perinatally MO-exposed adult animals in contrast to a reduced analgesic effect of MO measured in MO-exposed offspring after weaning and partly in adulthood. The reinforcing effect of MO in CPP, however, was significantly higher in the case of prenatal than postnatal MO exposure. While no SAL-exposed ‘control’ animals were studied in experiment II, comparing the results of experiments I and experiment II in the CPP test, it seems that MO exposure through the maternal milk did not influence the MO sensitivity of adult animals.
The enhanced reinforcing capacity of MO in perinatally MO-exposed animals is not surprising, although data in the literature are rather equivocal. While Riley and Vathy (2006) did not show enhanced rewarding properties, either in CPP or in self-administration in adult males exposed to MO prenatally, Ramsey et al. (1993) reported that prenatal MO exposure enhanced heroin and cocaine self-administration in adult males. Gagin et al. (1996, 1997) also reported enhanced sucrose preference and higher place preference for MO, both in males and females exposed to MO from GD 11 to 18, but sex differences were not found. In contrast, in our experiments, the enhanced reinforcing effect of MO was more marked in females. In addition, sex difference was also observed in perinatally SAL-exposed ‘control’ animals. According to Shoaib et al. (1995) 5 mg/kg MO induced a significant CPP in Wistar rats. In our CPP experiments we intended to choose MO doses, which do not induce strong reinforcing effects; therefore, we administered MO at doses of 1 and 3 mg/kg, which failed to induce place preference in perinatally SAL-exposed males. However, these doses of MO did induce a CPP in SAL-exposed females.
Though human data are rather controversial, females appear to be more vulnerable than males to the reinforcing effect of opiates, psychostimulants and nicotine during many phases of the addiction process, for example, acquisition, maintenance, disregulation-escalation, relapse (Lynch et al., 2002). In animal experiments female rats were found to be more vulnerable than males to the acquisition of cocaine and heroin self-administration (Lynch and Carroll, 1999). Mu-opioid receptor agonists showed higher reinforcing effect in females than in males (Cicero et al., 2003). Female rats discriminated MO at lower doses than males and acquired it in significantly fewer sessions (Craft et al., 1996). Sex difference was also reported by Vathy et al. (2007) for cocaine reward in adult animals exposed to MO from GD 11 to 18; however, prenatal MO exposure did not affect cocaine reward. All these data indicate that female rats are more sensitive to the rewarding effect of abused drugs.
The mechanism underlying the sex differences are not yet understood but sex-related alterations in pharmacokinetic characteristics do not seem to provide an explanation. Cicero et al. (1997) did not find sex-related differences in adult rats following single doses of MO in a range from 2.5 to 15 mg/kg, either in elimination half-life or in disappearance from the brain.
The elimination half life of MO alters in line with the age of pups: it was measured to be 2.5 h in neonates and 26 min in weanlings (Windh and Kuhn, 1995). However, no data were found in the literature about MO levels in the brain of pups exposed to MO pre or postnatally. Kunko et al. (1996) measured the methadone level in the brain of pups exposed to methadode either prenatally in utero or postnatally through maternal milk. While no detectable quantity was measured 4 days after parturition in the case of prenatal exposure, a measurable quantity of methadone was detected in the brain of pups exposed to it through maternal milk, but this decreased gradually as the pups aged. Even if the different pharmacokinetic properties of methadone are taken into consideration, we presume that the presence of MO in the brain of pups during prenatal or postnatal exposure may not qualitatively differ from that measured after methadone exposure.
Some studies suggested differences in the density of opioid receptors in the preoptic area in males and females (Hammer, 1984), or showed that adult females possess smaller μ-receptor reserve or less μ-receptor mediated signal transduction, than males (Craft et al., 2001). If perinatal MO exposure decreases the μ-receptor reserve in offspring, we may hypothesize that the same degree of change results in more marked consequences when the reserve is higher, and this may explain the more marked decrease in sensitivity to the antinociceptive effect of MO in males. The finding that the decrease of μ-receptor binding density in the preoptic area was more marked in perinatally MO-exposed males than in females (Hammer et al., 1991), supports this hypothesis. Other data (Windh et al., 1995; Stoller et al., 2002), however, speak against the role of receptor density in sex differences.
The long-term consequences of perinatal opioid exposure on transmitters and hormones, especially female gonadal hormones, are rather equivocal. A three-fold increase in dopamine (DA) content was measured in prenatally methadone-exposed females in the hypothalamus (Robinson et al., 1991) but not in the striatum (Vathy et al., 1994; Robinson et al., 1997) on PD 21. In contrast, Siddiqui et al. (1997) observed no changes in the DA level of the hypothalamus and amygdala in perinatally MO-exposed adult female rats. Sexually dimorphic alteration of norepinephrine level was observed in the hypothalamus of adult prenatally MO-exposed animals. Decreased levels were measured in females (Vathy and Katay, 1992; Siddiqui et al., 1997) but an increase was observed in males (Vathy and Katay, 1992) and similar (but not significant) sex difference was observed in frontal cortex. No change of norepinephrine content was reported in the striatum (Vathy et al., 1994) and in the amygdala (Siddiqui et al., 1997).
The effects of gonadectomy on sensitivity to the antinociceptive effects of morphine are rather inconsistent (Kepler et al., 1989; Candido et al., 1992; Ali et al., 1995). The role of gonadal hormones might be especially important when the reinforcing effect of MO is studied. In animal experiments female gonadal hormones enhance DA release in the striatum and in accumbens (Becker, 1999), the brain regions that mediate the positive reinforcing effects of abused drugs. Data obtained for humans with modern imaging techniques suggest that women have higher synaptic concentration of DA in the striatum, which may be associated with sex differences in vulnerability (Laakso et al., 2002).
As for the endocrinological consequences, Siddiqui et al. (1997) found reduced plasma estradiol, ovarian estradiol and ovarian progesterone levels in perinatally MO-exposed adult females, which indicates that the enhanced rewarding effect of MO cannot be explained simply by the changes in gonadal hormone system.
Summarizing, the major findings of the present paper are the followings:
- (1) We have found differences in the consequences of peri, pre and postnatal MO exposure according to the period of MO exposure. Birth weight of pups exposed to MO in utero was significantly lower. However, the weight gain after parturition was normal or even higher when the exposure was continued through maternal milk. In contrast, when the MO exposure started only after parturition through maternal milk, or when MO was withdrawn after parturition, the weight gain was slower.
- (2) Reduced sensitivity to the antinociceptive effect of MO was observed in the tail-flick test when the MO exposure occurred during the whole perinatal period.
- (3) Habituation to a new environment was slower in all the peri, pre or postnatally MO-exposed male pups.
- (4) Based on the CPP results, the enhanced sensitivity of peri or prenatally MO-exposed offspring to the rewarding effect of MO in adulthood might be considered as a predictive model of ‘vulnerability’.
In conclusion, while the procedure of MO exposure that we have used does not simulate exactly the drug-taking habits of pregnant women, we can state that even this relatively small, constant once-daily administration of MO during gestation and lactation results in long-term consequences in the offspring and may make them more vulnerable to MO abuse in adulthood.
Sponsorship: This study was supported by Hungarian grants OTKA K-60999 and ETT-441/2006.
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Keywords:© 2010 Lippincott Williams & Wilkins, Inc.
antinociception; conditioned place preference; morphine exposure; offspring; perinatal; rat; sex differences; tolerance