Injections of an opioid antagonist into the locus coeruleus and periaqueductal gray but not the amygdala precipitates morphine withdrawal in the 7‐day‐old rat

Jones, Kathy L.; Barr, Gordon A.

doi:10.1002/1098-2396(200102)39:2<139::aid-syn5>3.0.co;2-#

Cited by 9 publications

(9 citation statements)

References 32 publications

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“…Such sites include the locus coeruleus, hippocampus, cortex, caudate‐putamen (Jang et al, 2000), PAG, and the spinal cord (Jakowec et al, 1995a,b). Some of these sites are involved in morphine withdrawal in the infant (Jones and Barr, 2001). That the developing CNS expresses Ca 2+ ‐permeable AMPA receptors (Jakowec et al, 1995a,b; Pellegrini‐Giampietro et al, 1992) may also explain our finding that NBQX was effective in preventing the development of tolerance.…”

Section: Discussionmentioning

confidence: 99%

“…In the infant rat, models for assessing opiate tolerance and withdrawal have shown that: (1) when the behavioral repertoire appropriate to the age of the animal is examined, infant rat pups develop opiate tolerance and dependence (Jones and Barr, 1995); (2) the in vitro “isolated rat spinal cord” (Otsuka and Konishi, 1974) can been adapted to examine opiate tolerance and withdrawal in the week‐day‐old rat pups (Bell and Beglan, 1995a,b; Feng and Kendig, 1995; Zhu and Barr, 2003). These models of opiate tolerance and withdrawal in the infant rat have provided a stepping stone for understanding the neural mechanisms of opiate tolerance and withdrawal in developing organisms (Jones and Barr, 2001).…”

Section: Introductionmentioning

confidence: 99%

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The role of AMPA and metabotropic glutamate receptors on morphine withdrawal in infant rats

Zhu

Barr

2004

Intl J of Devlp Neuroscience

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Glutamate receptors, especially N-methyl-d-aspartate (NMDA) receptors, are hypothesized to play key roles in opiate tolerance and withdrawal. There is also accumulating evidence that alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists and group II metabotropic glutamate receptor (mGluR) agonists attenuate opiate withdrawal. However, most existing data are derived from adult animal models. Glutamate receptor types undergo dramatic developmental changes during early life. Thus, the pharmacological effects on opiate withdrawal of NMDA receptor, AMPA receptor, and mGluR antagonists in the developing organism may not be comparable to those in the adult. Indeed, NMDA receptor antagonists do not block morphine tolerance or withdrawal in the 7-day-old rat, but are partially effective in the 14-day-old, and fully effective in the 21-day-old. Thus, there is a transition period around the second post-natal week for NMDA receptor antagonists to suppress opiate tolerance and withdrawal. A combination of in vivo and in vitro assays was used in the present studies to test the effect of drugs acting on AMPA and group II mGlu receptors on morphine withdrawal in rats at 7, 14, and 21 days of age. These ages represent the critical periods when various glutamate receptor subunits undergo differential change. In contrast to NMDA receptor antagonists' early ineffectiveness in suppressing morphine withdrawal, the AMPA receptor antagonist and the group II mGluR agonists were effective at all ages tested. Thus, for the human infant patient, pharmacotherapies to reduce opiate tolerance and withdrawal should focus on non-NMDA ionotropic and metabotropic receptors.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The role of AMPA and metabotropic glutamate receptors on morphine withdrawal in infant rats

Zhu

Barr

2004

Intl J of Devlp Neuroscience

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“…In adult animals, the general consensus is that NMDA receptor antagonists inhibit the development, but not the expression, of opiate tolerance, dependence, and withdrawal (Trujillo 2000). An anatomical study was performed (Jones and Barr 2001) to determine whether the neural circuitry underlying adult opiate withdrawal (i.e., the LC, PAG, and the amygdala to a lesser extent) is similar in the neonate. It was demonstrated that injections of methylnaloxonium, a hydrophilic opioid receptor antagonist, into the LC and PAG, but not the amygdala, precipitated morphine withdrawal in neonatal rats at postnatal day (PND 1 ) 7.…”

Section: Glutamatergic Systemmentioning

confidence: 99%

Neonatal Animal Models of Opiate Withdrawal

Richardson¹,

Yohay²,

Gauda³

et al. 2006

ILAR Journal

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The symptoms of opiate withdrawal in infants are defined as neonatal abstinence syndrome (NAS). NAS is a significant cause of morbidity in term and preterm infants. Factors, such as polysubstance abuse, inadequate prenatal care, nutritional deprivation, and the biology of the developing central nervous system contribute to the challenge of evaluating and treating opiate-induced alterations in the newborn. Although research on the effects of opiates in neonatal animal models is limited, the data from adult animal models have greatly contributed to understanding and treating opiate tolerance, addiction, and withdrawal in adult humans. Yet the limited neonatal data that are available indicate that the mechanisms involved in these processes in the newborn differ from those in adult animals, and that neonatal models of opiate withdrawal are needed to understand and develop effective treatment regimens for NAS. In this review, the behavioral and neurochemical evidence from the literature is presented and suggests that mechanisms responsible for opiate tolerance, dependence, and withdrawal differ between adult and neonatal models. Also reviewed are studies that have used neonatal rodent models, the authors' preliminary data based on the use of neonatal rat and mouse models of opiate withdrawal, and other neonatal models that have been proposed for the study of neonatal opiate withdrawal.

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“…For example, morphine administration between P1-14 (Robinson et al, 2019) in mice induced neurodevelopmental delays, and effects on behaviors later during adolescence and adulthood, including marble burying and morphine locomotor sensitization behaviors (Robinson et al, 2019). Early neonatal opioid exposure in rodents has several key advantages: 1) opioid exposure during third trimester is associated with higher risk for NOWS in human neonates (Desai et al, 2015), providing strong translational relevance; 2) neonatal exposure during third trimester equivalent is sufficient to produce symptoms of withdrawal in mice and rats (Jones and Barr, 2001, 1995; McPhie and Barr, 2009; Robinson et al, 2019); 3) postnatal delivery of opioids enable accurate dosing to each pup; 4) avoiding maternal opioid exposure reduces the potential variance introduced by opioid-dependent alterations in maternal caretaking behaviors; and 5) the short-term and long-term effects of opioids on the brain and behavior can be assigned to a specific developmental period using discrete, timed administration of opioids.…”

Section: Introductionmentioning

confidence: 99%

“…Given these advantages, we employed a similar administration regimen as previously described (Robinson et al, 2019), to further investigate the consequences of neonatal opioid exposure in mouse model of NOWS, including ultrasonic vocalizations, anxiety and pain behaviors. To gain insight into the neurobiological adaptations related to NOWS, we also investigated the transcriptional alterations in the brainstem (medulla plus pons), a region of the brain implicated in neonatal opioid withdrawal (Jones and Barr, 2001; McPhie and Barr, 2009) (Maeda et al, 2002) and hyperalgesia (Bederson et al, 1990; Kaplan and Fields, 1991; Ossipov et al, 2005; Vanderah et al, 2001; Vera-Portocarrero et al, 2011; Xie et al, 2005). We used female and male outbred CFW mice (Swiss Webster) because of their increased genetic heterozygosity that better models humans (Tuttle et al, 2018), which can be leveraged in future studies to conduct high-resolution genetic mapping of NOWS-related phenotypes (Gonzales and Palmer, 2014; Parker et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Sex differences in behavioral and brainstem transcriptomic neuroadaptations following neonatal opioid exposure in outbred mice

Borrelli

Yao

Yen³

et al. 2021

Preprint

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The opioid epidemic led to an increase in the number of Neonatal Opioid Withdrawal Syndrome (NOWS) cases in infants born to opioid-dependent mothers. Hallmark features of NOWS include weight loss, severe irritability, respiratory problems, and sleep fragmentation. Mouse models provide an opportunity to identify brain mechanisms that contribute to NOWS. Neonatal outbred Swiss Webster Cartworth Farms White (CFW) mice were administered morphine (15mg/kg, s.c.) twice daily for postnatal days (P) 1-14, an approximate of the third trimester of human gestation. Male and female mice underwent behavioral testing on P7 and P14 to determine the impact of opioid exposure on anxiety and pain sensitivity. Ultrasonic vocalizations (USVs) and daily body weights were also recorded. Brainstems containing pons and medulla were collected during morphine withdrawal on P14 for RNA-sequencing. Morphine induced weight loss from P2-14, which persisted during adolescence (P21) and adulthood (P50). USVs markedly increased at P7 in females, emerging earlier than males. On P7 and P14, both morphine exposed female and male mice displayed hyperalgesia on the hot plate and tail flick assays, with females having greater hyperalgesia than males. Morphine-exposed mice exhibited increased anxiety-like behavior in the open-field arena at P21. Transcriptome analysis of the brainstem (medulla plus pons), an area implicated in opioid withdrawal and NOWS, identified pathways enriched for noradrenergic signaling in females and males. We also found sex-specific pathways related to mitochondrial function and neurodevelopment in females and circadian entrainment in males. Sex-specific transcriptomic neuroadaptations implicate unique neurobiological mechanisms underlying NOWS-like behaviors.

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Injections of an opioid antagonist into the locus coeruleus and periaqueductal gray but not the amygdala precipitates morphine withdrawal in the 7‐day‐old rat

Cited by 9 publications

References 32 publications

The role of AMPA and metabotropic glutamate receptors on morphine withdrawal in infant rats

The role of AMPA and metabotropic glutamate receptors on morphine withdrawal in infant rats

Neonatal Animal Models of Opiate Withdrawal

Sex differences in behavioral and brainstem transcriptomic neuroadaptations following neonatal opioid exposure in outbred mice

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