Next generation effects of female adolescent morphine exposure

Abstract

Prescription opiate use by adolescent girls has increased significantly in the past decade. Preclinical studies using rats report alterations in morphine sensitivity in the adult offspring of adolescent morphine-exposed females (MOR-F1) when compared with the offspring of adolescent saline-exposed females (SAL-F1). To begin to elucidate the development of these next generation modifications, the present study examined the effects of acute morphine administration on sedation and corticosterone secretion in prepubescent SAL-F1 and MOR-F1 male and female rats. In addition, alterations in proopiomelanocortin (POMC) gene expression in the arcuate nucleus, as well as in tyrosine hydroxylase (TH) and μ-opioid receptor (OPRM1) gene expressions in the ventral tegmental area, were analyzed using quantitative PCR, to determine whether differential regulation of these genes was correlated with the observed behavioral and/or endocrine effects. Increased morphine-induced sedation, coupled with an attenuation of morphine-induced corticosterone secretion, was observed in MOR-F1 males. Significant alterations in both POMC and OPRM1 gene expressions were also observed in MOR-F1 males, with no change in TH mRNA expression. Overall, these data suggest that the transgenerational effects of adolescent morphine exposure can be discerned before pubertal development and are more pronounced in males, and suggest dysregulation of the hypothalamic–pituitary–adrenal axis in the offspring of adolescent morphine-exposed females.

Transgenerational blunting of morphine-induced corticosterone secretion is associated with dysregulated gene expression in male offspring

“…Moreover, similar effects were observed in the F2 generation (derived from F1 females) [13]. More recently, we reported decreased corticosterone secretion in response to morphine in prepubertal MOR-F1 males [25]. Of note, no differences in corticosterone were observed in F1 females.…”

“…Using a model of female adolescent morphine exposure in rats (F0 generation), we have previously reported significant next generation effects in both male and female offspring [13, 14, 18, 23–25]. In all of our studies females were drug free for several weeks prior to mating.…”

Transgenerational attenuation of opioid self-administration as a consequence of adolescent morphine exposure

“…The observed reduction in self-administration behaviors, however, should not necessarily be interpreted as a demonstration of a “protective effect” on offspring and grandoffspring with regard to addiction liability. Indeed, other data from our lab suggest additional behavioral and molecular modifications in these animals that would be expected to increase their vulnerability to addiction under various conditions (Byrnes, 2005a, b, 2008; Byrnes et al, 2011; Byrnes et al, 2013; Johnson et al, 2011; Vassoler et al, 2014b; Vassoler et al, 2015). Thus, what we suggest is that maternal exposure to morphine during adolescence alters the neurodevelopment of future offspring that impacts how they respond to drugs of abuse, which may be dependent upon a host of environmental and genetic factors.…”

Exposure to opiates in female adolescents alters mu opiate receptor expression and increases the rewarding effects of morphine in future offspring

“…Previous work with this model has shown that there are alterations in various aspects of both behavior and physiology in the offspring. For example, it was shown that adult offspring from females exposed to morphine during adolescence demonstrate increased sensitivity to the analgesic properties of morphine, develop tolerance more rapidly, have alterations in play behavior, and dopamine D2 receptor sensitivity (Byrnes et al, 2011; Byrnes et al, 2013; Johnson et al, 2011; Vassoler et al, 2014). However, it is unclear if there are changes in the reward system in response to morphine.…”