Enduring consequences of perinatal fentanyl exposure in mice

Abstract

Opioid use by pregnant women is an understudied consequence associated with the opioid epidemic, resulting in a rise in the incidence of neonatal opioid withdrawal syndrome (NOWS) and lifelong neurobehavioral deficits that result from perinatal opioid exposure. There are few preclinical models that accurately recapitulate human perinatal drug exposure and few focus on fentanyl, a potent synthetic opioid that is a leading driver of the opioid epidemic. To investigate the consequences of perinatal opioid exposure, we administered fentanyl to mouse dams in their drinking water throughout gestation and until litters were weaned at postnatal day (PD) 21. Fentanyl‐exposed dams delivered smaller litters and had higher litter mortality rates compared with controls. Metrics of maternal care behavior were not affected by the treatment, nor were there differences in dams' weight or liquid consumption throughout gestation and 21 days postpartum. Twenty‐four hours after weaning and drug cessation, perinatal fentanyl‐exposed mice exhibited signs of spontaneous somatic withdrawal behavior and sex‐specific weight fluctuations that normalized in adulthood. At adolescence (PD 35), they displayed elevated anxiety‐like behaviors and decreased grooming, assayed in the elevated plus maze and sucrose splash tests. Finally, by adulthood (PD 55), they displayed impaired performance in a two‐tone auditory discrimination task. Collectively, our findings suggest that perinatal fentanyl‐exposed mice exhibit somatic withdrawal behavior and change into early adulthood reminiscent of humans born with NOWS.

Prenatal Methadone Exposure Disrupts Behavioral Development and Alters Motor Neuron Intrinsic Properties and Local Circuitry

“…Prior reports indicated opioid treatment alters maternal behavior which could impact offspring development 14,59 . However, we and others [60][61][62] , did not observe differences in maternal care suggesting the physical, behavioral, and neuronal differences found in offspring are a result of passive methadone exposure during gestational development.…”

Prenatal Opioid Exposure Enhances Responsiveness to Future Drug Reward and Alters Sensitivity to Pain: A Review of Preclinical Models and Contributing Mechanisms

“…The majority of preclinical studies have used rodent models, with rats being far more common than mice, although a few groups have employed mouse models ( Castellano and Ammassari-Teule, 1984 ; Mithbaokar et al, 2016 ; Kvello et al, 2019 ; Alipio et al, 2020 ; Robinson et al, 2020 ). Other animal models used sparingly include guinea pigs which have a placental structure more similar to humans and are born precocious (used by Olsen and colleagues; Nettleton et al, 2008 ; Wallisch et al, 2010 ) and chickens which have long been a model system for examining embryological development ( Schrott and Sparber, 2004 ; Lucas et al, 2010 ; Jiang et al, 2011 ; Wang et al, 2017 ).…”

“…Therefore, rodent studies of POE fundamentally cannot model placental opioid exposure during the third trimester of humans which is unfortunate because this is a period of continued central nervous development ( Semple et al, 2013 ). Many researchers assume that opioids are transferred via the breastmilk to offspring at pharmacologically relevant levels allowing continued opioid exposure postnatally ( Barr et al, 1998 ; Timár et al, 2010 ; Sithisarn et al, 2017 ; Alipio et al, 2020 ; Jantzie et al, 2020 ), but few studies are accompanied by adequate data on opioid concentrations in dams or offspring during this postnatal period. Studies which have assessed drug levels report fairly low opioid concentrations during the postnatal period ( Kunko et al, 1996 ; Kongstorp et al, 2019 ; Jantzie et al, 2020 ).…”

“…The opioid of choice in preclinical studies has typical been morphine or methadone likely because of their long history of clinical usage. The growing use of buprenorphine clinically and heroin, oxycodone, and fentanyl recreationally has also translated into their usage in preclinical models ( Robinson and Wallace, 2001 ; Chiang et al, 2010 ; Davis et al, 2010 ; Chiang et al, 2014 ; Devarapalli et al, 2016 ; Sithisarn et al, 2017 ; Wu et al, 2017 ; Griffin et al, 2019 ; Kvello et al, 2019 ; Wallin et al, 2019 ; Alipio et al, 2020 ). Less commonly used opioids, both clinically and preclinically, include the long acting methadone analogs l-α-acetylmethadol and N-desmethyl-l-α-noracetylmethadol ( Schrott and Sparber, 2004 ; Hamilton et al, 2005 ).…”

“…Additionally, minipumps and pellets provide a steady concentration of opioids which will not reflect the peaks and troughs in drug levels normally seen in pregnant women using opioids. A translational but often less practical solution is to provide dams with free access to opioids in drinking water allowing for oral consumption throughout pregnancy ( Ramsey et al, 1993 ; Nasiraei-Moghadam et al, 2010 ; Dehghani et al, 2013 ; Haydari et al, 2014 ; Alipio et al, 2020 ). While oral self-administration (SA) more accurately recapitulates the human condition, researchers lose the ability to control opioid exposure between experimental animals.…”