Mid- to late gestational morphine exposure does not alter the rewarding properties of morphine in adult male rats.

Prenatal exposure to drugs of abuse often leads to physiological and neurobiological abnormalities including decreased brain and body weight, cognitive deficits and behavioral alterations. A handful of studies showed increased vulnerability to drug abuse in prenatally drug-exposed offspring. Our work also demonstrated that prenatal exposure to analgesic doses of morphine during gestation days 11-18 increases mu-opioid receptor density in the nucleus accumbens and central amygdala of adult male rats. Both the nucleus accumbens and central amygdala play important roles in modulating drug-induced reward via the mesolimbic dopaminergic system. Therefore, two types of behavioral paradigms were used to test the hypothesis that the same prenatal morphine exposure would enhance the rewarding effects of morphine, making drug-exposed offspring more vulnerable to abuse this drug in adulthood. All experiments were performed with adult male offspring of saline-injected, morphine-injected or non-injected (control) dams. (1) The unbiased conditioned place preference (CPP) paradigm was used to investigate whether prenatal morphine exposure sensitizes adult male rats to non-contingent morphine reward. These adult animals were conditioned with 0.1, 0.3, 1, 3 or 5 mg/kg morphine. All control, prenatally saline- and morphine-exposed male rats preferred the morphine-paired compartment relative to the saline-paired compartment. However, the magnitude of morphine CPP in adult male rats was not dependent on the conditioning dose of morphine or prenatal morphine exposure. (2) Intravenous morphine self-administration was used to assess the behavioral response to contingent morphine reward. Each rat self-administered one of four doses of morphine (0.3, 1, 2 or 3 mg/kg/infusion). Morphine self-administration was not altered in prenatally morphine-exposed adult male offspring. Control males self-administered significantly less morphine at the lowest dose of morphine than both prenatally saline- and morphine-exposed males. Although our data show that prenatal exposure to an analgesic dose of morphine during the time of opioid receptor appearance does not enhance morphine CPP or self-administration, they do not exclude the possibility that this prenatal morphine exposure enhances the rewarding properties of other drugs of abuse.

Autoradiographic evidence that prenatal morphine exposure sex-dependently alters mu-opioid receptor densities in brain regions that are involved in the control of drug abuse and other motivated behaviors.

The present study examined the effects of prenatal morphine exposure on mu-opioid receptor density in young adult male and female rats to assess the long-term alterations in several brain areas including the nucleus accumbens (NAc), bed nucleus of stria terminalis (BNST), and the basolateral (BLA), lateral (LA), central (CeA), and posteromedial cortical (PMCoA) amygdaloid nuclei. These brain areas are involved in motivating and rewarding behaviors of opiates and other drugs of abuse. The reinforcing actions of opiates appear to be mu-opioid receptor dependent. The results demonstrate that in male rats, prenatal morphine exposure significantly increases the density of mu-opioid receptors in the NAc and PMCoA. In contrast, the same prenatal morphine exposure reduces the density of mu-opioid receptors in the BLA, while increasing it in the CeA and without effects in the LA or BNST. In female rats, prenatal morphine exposure has no effects on the density of mu-opioid receptors in the above six brain areas, but the density of these receptors is dependent on the presence or absence of ovarian hormones. Thus, the present study demonstrates that mid- to late gestational morphine exposure induces long-term, sex-specific alterations in the density of mu-opioid receptors in the NAc and amygdala. Moreover, this prenatal morphine exposure also eliminates sex differences in the density of mu-opioid receptors in the NAc, CeA, and PMCoA but not in the BLA, LA, and BNST.

Mu-opioid receptors in seizure-controlling brain structures are altered by prenatal morphine exposure and by male and female gonadal steroids in adult rats.

The present study used autoradiography to examine the effect of prenatal morphine exposure on mu-opioid receptor density in epileptic seizure-controlling brain structures including the substantia nigra pars compacta (SNC), substantia nigra pars reticulata (SNR), superior colliculus (SC), and subthalamic nucleus (STN) of adult male and female rats. The results demonstrate that prenatal morphine exposure increases the mu-opioid receptor density in the SNC and STN, but not in the SNR or in the SC of gonadally intact adult male rats. The density of mu-opioid receptors in the SNC and STN is, however, decreased following gonadectomy in morphine-exposed males, and testosterone treatment fails to restore this decrease to the level of gonadally intact males. Further, in the SC, the density of mu receptors was lower in both saline-exposed, gonadectomized (GNX) and GNX, TP-treated males and in morphine-exposed, GNX, TP-treated males relative to gonadally intact saline- and morphine-exposed males, respectively. In ovariectomized (OVX) female rats, the same prenatal morphine exposure increases the mu-opioid receptor density in the SNC and SNR, but decreases it in the STN. The density of mu-opioid receptors is also decreased in the SNC and SC of OVX estrogen-treated females and in the SNR and SC of OVX, progesterone-treated females. Thus, the present study demonstrates that mu-opioid receptors in seizure-controlling brain structures are sex-specifically altered by prenatal morphine exposure in adult progeny. Further, prenatal morphine exposure alters gonadal hormone effects on the density of mu receptors in adult, OVX females.

The relationship between adult health and childhood maltreatment, as moderated by anger and ethnic background.

Childhood maltreatment, anger, and racial/ethnic background were examined in relation to physical health, psychological well-being, and blood pressure outcomes. This study used data from a diverse sample of African American, Latino, and Caucasian participants (N=198). Results from a series of multiple regressions indicated anger and total childhood maltreatment were robust predictors of poorer health. Although correlational analyses found maltreatment from the mother and father were associated with poorer health outcomes, when considered as part of the regression models, only a relationship between maltreatment from the mother and physical health was found. Greater anger scores were linked with lower blood pressure, particularly systolic blood pressure. Generally, more psychological and physical symptom reporting was found with greater anger scores, and higher levels of total maltreatment also predicted physical symptoms. The pattern of interactions indicated anger was more detrimental for African American participant's (and marginally so for Latino participant's) physical health. Interestingly, interactions also indicated total childhood maltreatment was related to fewer symptoms for Latino participants. Although child maltreatment may be viewed as a moral and/or human rights issue, this study provides evidence that it can also be viewed as a public health issue. Our study demonstrated that known health risk factors such as anger and maltreatment may operate in a different pattern dependent on ethnic/cultural background. The findings suggest health and health disparities research would benefit from greater exploration of the differential impact of certain moderating variables based on racial/ethnic background.

Adrenocorticotropin stress response but not glucocorticoid-negative feedback is altered by prenatal morphine exposure in adult male rats.

The present study was designed to investigate the effects of prenatal morphine exposure on the hypothalamic-pituitary-adrenal (HPA) axis-regulated stress responses by measuring restraint stress-induced changes in the adrenocorticotropic hormone (ACTH) and corticosterone (CORT) levels. In experiment 1, plasma levels of ACTH and CORT in prenatally morphine-, saline-exposed and control male rats were determined before and at several times after restraint stress. There were no statistically significant differences in plasma ACTH and CORT levels before restraint stress between the groups. However, prenatal morphine exposure dampened the stress-induced increase and spontaneous recovery of ACTH levels after the restraint stress. There were no differences in plasma CORT levels between the three groups either before or at any time after restraint stress. Experiment 2 was designed to investigate the sensitivity of negative feedback of glucocorticoids using the dexamethasone (DEX) suppression test. DEX was administered at different doses (0.001, 0.01, 0.1 and 1.0 mg/kg) and ACTH and CORT plasma levels were measured before and at several times after restraint stress in prenatally morphine- and saline-exposed males. DEX pretreatment eliminated the differences observed in ACTH responses to stress in morphine- and saline-exposed males. DEX pretreatment dose dependently suppressed the restraint stress-induced increased plasma ACTH concentration. In plasma CORT levels, DEX pretreatment dose dependently suppressed the restraint stress-induced increased plasma CORT concentration regardless of prenatal drug exposure. Thus, the present study demonstrates that prenatal morphine exposure alters the ACTH and CORT responses to stress but not the sensitivity of negative feedback of glucocorticoids.

Hypothalamo-pituitary-adrenal axis-regulated stress response and negative feedback sensitivity is altered by prenatal morphine exposure in adult female rats.

It has been shown that adult female rats react to stressors more intensely than adult male rats. Our previous work demonstrated that the adrenocorticotropic hormone (ACTH) but not corticosterone (CORT) response to stress is altered by prenatal morphine exposure in adult male rats. Response of the hypothalamo-pituitary-adrenal (HPA) axis to stress is known to be sex specific and dependent on the hormonal fluctuation of the estrous cycle. Therefore, the present study examined the effect of prenatal morphine exposure on the levels of ACTH and CORT before and after restraint stress in adult female rats. Experiment 1 tested ACTH and CORT plasma levels before and after restraint stress in prenatally morphine- and saline-exposed, adult diestrus and proestrus female rats. Prenatal morphine exposure suppressed the restraint stress-induced ACTH levels in both diestrus and proestrus females, but did not have any effects on the basal or stress-induced CORT levels. Experiment 2 examined the sensitivity of negative feedback using the dexamethasone (DEX) (0.001, 0.01, 0.1 and 1.0 mg/kg) suppression test in adult, prenatally morphine- and saline-exposed female rats. In saline-exposed, proestrus but not diestrus females, all doses of DEX were effective in suppressing the restraint stress-induced increase in CORT levels. In both diestrus and proestrus, morphine-exposed females, only the two highest doses of DEX (0.1 and 1.0 mg/kg) were successfully suppressing the stress-induced CORT levels. The stress-induced increase in the ACTH level was suppressed only by the highest dose of DEX (1.0 mg/kg) in both saline- and morphine-exposed, diestrus and proestrus females. Thus, the present study demonstrates that prenatal morphine exposure alters the HPA axis-regulated stress response and the sensitivity of negative feedback that are affected by the fluctuation of ovarian hormones.