Susanna Gyarmati

Peri, pre and postnatal morphine exposure: Exposure-induced effects and sex differences in the behavioural consequences in rat offspring

This study investigated the behavioural consequences of peri, pre and postnatal morphine (MO) exposure in rats. From gestational day 1 dams were treated with either saline or MO subcutaneously once a day (5 mg/kg on the first 2 days, 10 mg/kg subsequently). Spontaneous locomotor activity in a new environment (habituation) and antinociceptive effects of MO were measured separately in male and female pups after weaning and also in late adolescence or adulthood. The rewarding effect of MO was assessed by conditioned place preference in adult animals. Both exposure-induced and sex differences were observed. A significant delay in habituation to a new environment and decreased sensitivity to the antinociceptive effect of MO were found in male offspring of MO-treated dams. In contrast, the place preference induced by MO was enhanced in the MO-exposed adult animals and this effect was more marked in females. Prenatal exposure to MO resulted in more marked changes than the postnatal exposure through maternal milk. The results indicate that a medium MO dose administered once-daily results in long-term consequences in offspring and may make them more vulnerable to MO abuse in adulthood.

Spinal interaction between the highly selective μ agonist DAMGO and several δ opioid receptor ligands in naive and morphine-tolerant mice.

Since the discovery of opioid receptor dimers their possible roles in opioid actions were intensively investigated. Here we suggest a mechanism that may involve the μ-δ opioid heterodimers. The exact role of δ opioid receptors in antinociception and in the development of opioid tolerance is still unclear. While receptor up-regulation can be observed during the development of opioid tolerance no μ receptor down-regulation could be detected within five days. In our present work we investigated how the selective δ opioid receptor agonists and antagonists influence the antinociceptive effect of the selective μ receptor agonist DAMGO in naïve and morphine-tolerant mice. We treated male NMRI mice with 200 μmol/kg subcutaneous (s.c.) morphine twice daily for three days. On the fourth day we measured the antinociceptive effect of DAMGO alone and combined with delta ligands: DPDPE, deltorphin II (agonists), TIPP and TICPψ (antagonists), respectively, administered intrathecally (i.t.) in mouse tail-flick test. In naive control mice none of the δ ligands caused significant changes in the antinociceptive action of DAMGO. The treatment with s.c. morphine resulted in approximately four-fold tolerance to i.t. DAMGO, i.e. the ED₅₀ value of DAMGO was four times as high as in naive mice. 500 and 1000 pmol/mouse of the δ₁ selective agonist DPDPE enhanced the tolerance to DAMGO while 1000 pmol/mouse of the δ₂ selective agonist deltorphin II did not influence the degree of tolerance. However, both δ antagonists TIPP and TICPψ potentiated the antinociceptive effect of i.t. DAMGO, thus they restored the potency of DAMGO to the control level. The inhibitory action of DPDPE against the antinociceptive effect of DAMGO could be antagonized by TIPP and TICPψ. We hypothesize that during the development of morphine tolerance the formation of μδ heterodimers may contribute to the spinal opioid tolerance. δ ligands may affect the dimer formation differently. Those, like DPDPE may facilitate the dimer formation hence inhibit the antinociceptive effect of DAMGO by causing virtual μ receptor down-regulation. Ligands that do not affect the dimer formation do not influence antinociception either but ligands with the presumed capability of disconnecting the dimers may decrease the spinal tolerance to DAMGO.

Does the effect of morphine challenge change on maternal behaviour of dams chronically treated with morphine during gestation and further on during lactation

Opioids impair the maternal behaviour of rats. The effect of morphine on maternal behaviour in dams treated chronically with morphine during the whole pregnancy and lactation has not been analysed systematically. The aim of the present study was to investigate the possible differences in the disruptive effect of morphine on maternal behaviour following morphine challenges between dams treated chronically with saline or morphine during gestation and postpartum. The antinociceptive action of morphine was also studied in dams. The disruptive effect of morphine on maternal behaviour was not changed as the postpartum period passed. The duration of this effect of morphine lasted for about 2h. The dose-dependent disruptive effect of acute doses of morphine on maternal behaviour was more marked in the morphine-treated dams, than in the saline-treated ones, indicating a tendency for sensitisation to this effect. A trend for tolerance was observed to the antinociceptive effect of morphine in animals treated daily with morphine during the entire gestational and lactation periods; however, this difference did not reach statistical significance. Our experimental protocol might be a predictive model of human opioid abuse. Sensitisation to the impairing effect of opiates on maternal behaviour may explain why a mother abusing heroin neglects her baby even if she does not experience euphoria.

The anorectic effect of satietin is unrelated to carbohydrate metabolism

The effect of satietin and amphetamine on the carbohydrate metabolism of free fed and food deprived rats was studied. Rats deprived of food for 96 hours maintained normal glucose and glucagon blood levels but the blood concentration of insulin dropped from 232.02 +/- 23.93 to 12.48 +/- 0.71 pmol/l. Amphetamine (500 micrograms/animal, intracerebroventricularly) left in normally fed rats the blood concentration of glucose, insulin and glucagon unchanged. The same treatment, however, increased the insulin concentration in the blood of food deprived rats from 11.37 +/- 4.43 to 73.47 +/- 8.29 pmol/l. Glucose and glucagon, as well as insulin levels remained unchanged in both normally fed and food deprived rats when treated with satietin (20 micrograms/rat, intracerebroventricularly). It was concluded that the anorectic effect of satietin is unrelated to carbohydrate metabolism.

Behavioural sensitisation of rat dams treated with morphine pre- and postpartum

Background In our previous experiments a trend to sensitisation to maternal behavioural disruptive and conditioned place preference (CPP)-inducing effects of morphine (MO) was observed when rat dams were treated chronically with a constant medium dose of MO during pregnancy and lactation. The aim of the present work was to perform more detailed studies how chronic MO treatment of dams influences behavioural effects of subsequent MO challenge.

Changes in stereotyped behaviour following acute or repeated methylenedioxy-methamphetamine (MDMA) treatment

Results (1) Following repeated administration of d-MDMA the intensity of MDMA-induced HTS decreased while that of SB increased. (2) Single dose pretreatment with d-MDMA did not influence the d-MDMA-induced HTS but enhanced the SB. (3) The d-AM-induced SB also increased while the APO-induced SB did not change. Conclusion A single dose of d-MDMA, which, in contrast to the repeated treatment, did not alter the 5-HT-related behaviour, may already result in development of DA sensitization.

Changes in the action of morphine challenge following perinatal morphine exposure in rats

Methods Pregnant Wistar rats were treated daily with MO (10 mg/ kg s.c.) from the day of mating until weaning (post partum day [PD] 21). Spontaneous MB (active nursing, passive nursing, littering and behaviours out of the nest) was checked on the 2nd, 3rd, 5th, 7th and 9th PDs. Analgesic affect of MO was measured in tail-flick test in the offspring on PD 23. Conditioned place preference (CPP) inducing effect of MO was checked in adult offspring.