Melinda Sobor

Changes in adaptability following perinatal morphine exposure in juvenile and adult rats

The problem of drug abuse among pregnant women causes a major concern. The aim of the present study was to examine the adaptive consequences of long term maternal morphine exposure in offspring at different postnatal ages, and to see the possibility of compensation, as well. Pregnant rats were treated daily with morphine from the day of mating (on the first two days 5mg/kgs.c. than 10mg/kg) until weaning. Male offspring of dams treated with physiological saline served as control. Behavior in the elevated plus maze (EPM; anxiety) and forced swimming test (FST; depression) as well as adrenocorticotropin and corticosterone hormone levels were measured at postpartum days 23-25 and at adult age. There was only a tendency of spending less time in the open arms of the EPM in morphine treated rats at both ages, thus, the supposed anxiogenic impact of perinatal exposure with morphine needs more focused examination. In response to 5min FST morphine exposed animals spent considerable longer time with floating and shorter time with climbing at both ages which is an expressing sign of depression-like behavior. Perinatal morphine exposure induced a hypoactivity of the stress axis (adrenocorticotropin and corticosterone elevations) to strong stimulus (FST). Our results show that perinatal morphine exposure induces long term depression-like changes. At the same time the reactivity to the stress is failed. These findings on rodents presume that the progenies of morphine users could have lifelong problems in adaptive capability and might be prone to develop psychiatric disorders.

The central versus peripheral antinociceptive effects of μ-opioid receptor agonists in the new model of rat visceral pain

This study describes the antinociceptive effects of μ-opioid agonists, d-Ala(2),N-Me-Phe(4),Gly(5)-ol-enkephalin (DAMGO) and morphine in a model of rat visceral pain in which nociceptive responses were triggered by 2% acetic acid intraperitoneal (i.p.) injections. DAMGO and morphine were administered i.p., to the same site where acetic acid was delivered or intracerebroventricularly (i.c.v.). The antinociceptive actions of i.p. versus i.c.v. administered DAMGO or morphine were evaluated in the late phase of permanent visceral nociceptive responses. Both compounds inhibited the nociceptive responses in a dose-dependent manner and exhibited more potent agonist activity after i.c.v. than i.p. administration. DAMGO and morphine showed comparable ED(50) values after i.p. injections. However, DAMGO was much stronger than morphine after central administration. Co-administration of the peripherally restricted opioid antagonist, naloxone methiodide (NAL-M), significantly attenuated the antinociceptive effects of i.p. DAMGO or morphine. On the other hand, i.c.v. injections of NAL-M partially antagonized the antinociceptive effect of i.p. morphine and failed to affect the antinociceptive action of i.p. DAMGO indicating the partial and pure peripheral antinociceptive effects of morphine and DAMGO, respectively. These results suggest the role of either central or peripheral μ-opioid receptors (MOR) in mediating antinociceptive effects of i.p. μ-opioid agonists in the rat late permanent visceral pain model which closely resembles the clinical situation.

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.

Novel approach to demonstrate high efficacy of μ opioids in the rat vas deferens: A simple model of predictive value

14-O-Methyloxymorphone and 14-methoxymetopon were reported as highly selective and potent micro opioid receptor agonists. The aim of this study was to demonstrate the opioid activity of these compounds in vitro and in vivo in comparison to oxymorphone, morphine and DAMGO. The micro opioid receptor efficacy, full or partial agonist nature of opioids was analyzed in the rat vas deferens (RVD) bioassay. Compared to oxymorphone, 14-O-methyloxymorphone and 14-methoxymetopon showed greater affinities to the rodent brain micro opioid receptors in receptor binding assays. In isolated organs 14-O-methyloxymorphone and 14-methoxymetopon were 3-10-fold more potent than the micro agonist opioid peptide, DAMGO. All tested compounds reached at least 70% maximum inhibition in mouse vas deferens (MVD) except morphine and oxymorphone. In the RVD, morphine could not exceed 50% inhibition of the twitches while 14-O-methyloxymorphone and 14-methoxymetopon showed inhibitory effects more than 70%. Oxymorphone reached only 4% maximal agonist effect and antagonized the inhibitory effect of DAMGO. The investigated morphinans produced dose-dependent antinociceptive activities in mice and rats. Both, 14-O-methyloxymorphone and 14-methoxymetopon are highly efficacious micro opioid receptor agonists in the RVD exhibiting full micro agonist properties. The RVD tissue contains mu receptors indicated by the comparable K(e) values of the micro antagonist naltrexone against DAMGO in the MVD. RVD may be a good alternative to assess the mu receptor efficacy of opioid agonists providing a more physiological environment for the ligand-receptor interaction than other efficacy measuring methods such as the [(35)S]GTPgammaS binding assay.

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.

Spinal interaction between μ and δ opioid receptors in naive and morphine-tolerant rats

Background The role of δ opioid receptors in opioid antinociception and tolerance development is still unclear. In the spinal cord of morphine-tolerant mice δ receptor ligands given intrathecally (i.t.) differently influenced the antinociceptive effect of the μ agonist D-Ala2-methyl-glycinol (DAMGO). The δ1 agonist D-Pen2,5-enkephalin (DPDPE) inhibited, the δ2 agonist deltorphin II did not alter, and the δ antagonist cha-TIPPψ potentiated the effect of DAMGO. We hypothesized that during the development of morphine tolerance the formation of μ-δ heterodimers may contribute to the spinal μ opioid tolerance. Delta 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 but ligands with the presumed capability of disconnecting the dimers may decrease the spinal tolerance to DAMGO. The δ ligand profile in morphine-tolerant rats, were also studied.

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.