Oxycodone self-administration during pregnancy disrupts the maternal-infant dyad and decreases midbrain OPRM1 expression during early postnatal development in rats
Introduction
Recent data from the Centers for Disease Control (CDC) reveal that women of reproductive age are frequently prescribed opioid pain medications, with 39% of Medicaid and 28% of privately insured female patients between the ages of 15–44 filling at least one prescription each year (http://www.cdc.gov/media/releases/2015/p0122-pregnancy-opioids.html, 2015). These findings led the CDC to recommend that physicians carefully consider the appropriateness of treating women who are pregnant, or may become pregnant, with opioids due to the risk of potential birth defects, including the risk of neonatal abstinence syndrome (NAS). Data regarding birth defects associated with gestational opioids are extremely limited, particularly regarding commonly prescribed opioids, like codeine or oxycodone. It is clear, however, that the rates of prenatal opioid exposure are rising with recent reports suggesting a 5 fold increase in maternal opioid use from 2000 to 2009 and a 3 fold increase in infants born to women dependent on, or addicted to, prescription opioids (Patrick et al., 2012). The extent to which rising rates of opioid prescriptions in women are related to these outcomes is open for debate; however, it should be noted that states with the highest number of opioid prescriptions are also those with the highest number of infants born with NAS (Patrick et al., 2015). Moreover, rates of prescription opioid misuse and opioid use disorder remain stubbornly high despite efforts to improve prescribing habits. Indeed, the number of women misusing prescription opioids is substantially higher than the number addicted to heroin (Han et al., 2017). Thus, prenatal exposure to prescription opioids, the growing population of NAS infants, and the potential long-term neurodevelopment effects of both exposure and withdrawal remain significant areas of concern.
Most animal models of prenatal opioid exposure have examined the effects of morphine. Many rely on either continuous release pumps/pellets or experimenter administered drug, neither of which is representative of human use. There are a few studies that have used oral gavage or delivery via the animal's water-bottle to replicate oral ingestion of pain medication (Nasiraei-Moghadam et al., 2005; Schrott et al., 2008; Davis et al., 2010), however, those studies must consider potential issues related to first-pass metabolism (Iwamoto and Klaassen, 1977) which may be further complicated by the increased circulatory demands of pregnancy. Finally, the vast majority of studies begin their opioid administration on or around the first day of pregnancy, a model which does not represent the likely pattern of use in women.
Drug self-administration represents an animal model with high face, construct, and predictive validity with regard to the abuse liability of compounds across drug class. By training the animal to perform a specific operant response to attain an intravenous drug infusion, this paradigm allows the animal to control the timing and amount of drug intake. Studies have demonstrated significant differences between this type of voluntary drug intake, when compared to both experimenter administered and non-contingent drug infusion across a number of different drugs (Jacobs et al., 2003). These differential effects are observed on measures of withdrawal, gene expression and neurochemical effects in a number of critical brain regions (Mutschler and Miczek, 1998; Miguens et al., 2008; Orejarena et al., 2009; Metaxas et al., 2010). Of particular relevance to modeling drug use during pregnancy, significant alterations in both endocrine and immune function are observed following opioid self-administration that are not similarly observed following with the same amounts of opioids administered using non-contingent infusions (Weber et al., 2009). These differences could impact how prenatal opioid exposure affects both the mother and her offspring.
The purpose of the current set of studies was to utilize a model of prenatal oxycodone self-administration in rats to examine the impact of voluntary intake on both the dam and her offspring during the early postnatal period. As there are currently no published data on opioid self-administration during pregnancy, we first determined whether the rate of responding for a moderate dose of oxycodone was altered by the state of pregnancy. We also examined the effects of oxycodone prior to mating on fertility and fecundity. We then examined the effects of prenatal oxycodone self-administration on response rates following postpartum drug withdrawal as well as on maternal responding and developmental parameters in offspring, including effects on body weight and number of separation-induced ultrasonic vocalizations. Finally, we examined mu opioid receptor gene (OPRM1) expression in three regions of the developing brain (postnatal day 1; brainstem, hypothalamus, and forebrain) as modifications in the regulation of this gene are correlated with increased risk of neonatal abstinence syndrome (Wachman et al., 2013; Wachman et al., 2014). Indeed, OPRM 1 expression is of interest because it's role in withdrawal and correlation with the severity of neonatal abstinence syndrome. In addition, stimulation of this receptor in utero may have a profound impact on subsequent gene expression which could alter neurodevelopmental trajectories for the offspring.
Section snippets
Animals
Nulliparous female Sprague-Dawley rats (approximately 70 days of age) were purchased from Charles River Breeding Laboratories (Kingston, NY, USA) and housed in a light (0700–1900 h) and temperature (21–24 °C) controlled room. Food and water were provided ad libitum throughout the experiment. All procedures were conducted in accordance with the National Research Council (NRC) Guide for the Care and Use of Laboratory Animals and approved by the Institutional Animal Care and Use Committee at Tufts
Female oxycodone self-administration as a function of reproductive status
As shown in Fig. 1a, females readily learn to press for oxycodone (0.1 mg/kg) during the 1 h access period, with all females demonstrating increased numbers of presses on the active versus the inactive lever by the fifth session (Main Effect of Day F[14,504] = 2.16, p < 0.01; Main Effect of Response Lever F[1,36] = 10.5, p < 0.01; Day by Response Lever Interaction F[14,504] = 3.05, p < 0.01). After 15 sessions, a subset of females were mated with males. Data comparing the active lever
Discussion
The current set of findings demonstrate the feasibility of modeling voluntary opioid use during gestation using i.v. self-administration. Given the significant physiological changes observed during pregnancy, including dramatic fluctuations in circulating hormones (Soma-Pillay et al., 2016), we first examined whether pregnancy would alter the amount of oxycodone females self-administered. When compared to cycling females, no differences in daily intake of oxycodone were observed as a function
Conclusions
The current set of findings demonstrates the feasibility and utility of using i.v. self-administration to study prenatal oxycodone use. The data suggest significant effects of oxycodone on both the dam and pup at doses that are voluntarily self-administered throughout pregnancy. The use of i.v. administration, as opposed to oxycodone in water bottles, avoids the significant issues of first pass metabolism which is more robust in females, resulting in poor bioavailability (Chan et al., 2008).
Authors' contributions and funding source
EMB and FMV were responsible for the study concept and design. MLO and FMV contributed to the acquisition of animal data. AT performed the gene expression analyses. All authors contributed to the analyses of data. EMB interpreted the findings and drafted the manuscript. FMV and AT provided critical revision of the manuscript for intellectual content. All authors reviewed the content and approved the final version for publication. This work was funded by NIH awards 5R01DA025674 and 5T35RR029724.
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