The effect of pituitary adenylate cyclase-activating polypeptide on elevated plus maze behavior and hypothermia induced by morphine withdrawal

Lipták, Nándor; Dochnal, Roberta; Babits, Anikó; Csabafi, Krisztina; Szakács, Júlia; Tóth, Gábor; Szabó, Gyula

doi:10.1016/j.npep.2011.12.001

Cited by 8 publications

(7 citation statements)

References 39 publications

(52 reference statements)

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“…In the current report, we showed that mice undergoing NAL‐precipitated MOR withdrawal exhibit an increase in the time spent and entries to the open‐arms of the EPM in accordance with previous studies (Hodgson et al, ; Hofford et al, ; Lipták et al, ). The interpretation of these results is quite controversial but, a recent report by Lipták et al, () has shown that mice undergoing NAL‐precipitated MOR withdrawal spent significantly more time and traveled significantly more distance in the center of the open field compared to the control mice confirming the results observed in the EPM.…”

Section: Discussionsupporting

confidence: 93%

“…mice develop a MOR dependence without altering its behavior (Diaz et al, ). The dependence state did not modify EPM behaviors for either sex in accordance with previous reports (Lipták et al, ; Zhang and Schulteis, ). We used NAL (6 mg/kg, i.p.)…”

Section: Discussionsupporting

confidence: 92%

“…Thus, the EPM behaviors of withdrawn mice could indicate an increased motivation to scape that induces exploration and/or risk‐taking behaviors similar to the behaviors observed in addicts (Hodgson et al, ). Interestingly, all studies performed in mice show an anxiolitic‐like behavior during naloxone‐precipitated morphine withdrawal in the EPM test (Buckman et al, 2008; Hofford et al, ; Lipták et al, ). However, studies performed in rats (Zhang et al, 2008) show an anxiety‐like behavior.…”

Section: Discussionmentioning

confidence: 99%

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Baclofen prevents the elevated plus maze behavior and BDNF expression during naloxone precipitated morphine withdrawal in male and female mice

Pedrón

Varani

Balerio

2016

Synapse

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In previous studies we have shown that baclofen, a selective GABAB receptor agonist, prevents the somatic expression and reestablishes the dopamine and μ-opioid receptors levels, modified during naloxone-precipitated morphine withdrawal syndrome in male and female mice. There are no previous reports regarding sex differences in the elevated plus maze (EPM) and the expression of BDNF in morphine-withdrawn mice. The present study analyses the behavioral and biochemical variations during morphine withdrawal in mice of both sexes, and whether these variations are prevented with baclofen. Swiss-Webster albino prepubertal mice received morphine (2 mg/kg, i.p.) twice daily, for 9 consecutive days. On the 10th day, one group of morphine-treated mice received naloxone (opioid receptor antagonist; 6 mg/kg, i.p.) 1 h after the last dose of morphine to precipitate withdrawal. A second group received baclofen (2 mg/kg, i.p.) before naloxone administration. The EPM behavior was measured during 15 min after naloxone injection. The expression of BDNF-positive cells was determined by immunohistochemistry. Withdrawn male mice showed a higher percentage of time spent and number of entries to the open arms compared to withdrawn female mice. Baclofen prevented this behavior in both sexes. BDNF expression decreased in the AcbC, BNST, CeC, and CA3 of the hippocampus while increased in the BLA of morphine withdrawn male. Baclofen pretreatment prevented the BDNF expression observed in morphine withdrawn male mice in all the brain areas studied except in the CeC. Baclofen prevention of the EPM behavior associated to morphine withdrawal could be partially related to changes in BDNF expression.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

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Baclofen prevents the elevated plus maze behavior and BDNF expression during naloxone precipitated morphine withdrawal in male and female mice

Pedrón

Varani

Balerio

2016

Synapse

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“…Importantly, circadian genes, such as Per3 , which was changed in morphine-exposed male mice, have been associated with opioid-induced hyperalgesia in mice ( Zhang et al, 2019 ) and mutations in PER3 are associated with opioid dependence in humans ( Surovtseva et al, 2012 ). Other genes that were upregulated in morphine-exposed males include the PACAP1 receptor and ryanodine receptors, which are also associated with opioid withdrawal ( Ohsawa and Kamei, 1999 ; Mácsai et al, 2002 ; Martin et al, 2003 ; Lipták et al, 2012 ).…”

Section: Discussionmentioning

confidence: 99%

Sex Differences in Behavioral and Brainstem Transcriptomic Neuroadaptations following Neonatal Opioid Exposure in Outbred Mice

Borrelli

Yao

Yen

et al. 2021

eNeuro

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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. Female and male 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 showing greater hyperalgesia than males. Morphine-exposed mice exhibited increased anxiety-like behavior in the open-field arena on P21. Transcriptome analysis of the brainstem, 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. 3 SIGNIFICANCE STATEMENTNeonatal opioid withdrawal syndrome (NOWS) is a poorly understood condition that has both a genetic and environmental component and is thought to be mechanistically distinct from opioid withdrawal in adults. The development of murine models for measuring neurobehavioral responses is critical for informing the neurobiological adaptations underlying NOWS. Using outbred mice that more closely model human genetic variation, we discovered several sex differences in behavioral timing and severity of NOWS-model behaviors as well as transcriptomic adaptations in brain tissue that together suggest distinct mechanisms and sex-specific therapeutics for reversing withdrawal symptoms and restoring brain function.

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“…While changes in body temperature have not been well characterized in rodent models of NOWS, a 2019 study showed that body temperature decreased following prenatal opioid exposure (Wallin et al, 2019). Additionally, studies in adult rodent models of opioid withdrawal have also reported a decrease in body temperature (Belknap, 1989;Lipt ak et al, 2012). In contrast to these previous reports, the body temperature of spiny mice pups from the morphine exposed groups was significantly higher in both sexes.…”

Section: Discussionmentioning

confidence: 94%

Opioid withdrawal behavior in spiny mice: A novel preclinical model of neonatal opioid withdrawal syndrome (NOWS)

Stevens

Mohan

2021

Heliyon

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As the opioid epidemic continues to grow, opioid use among pregnant women is increasing significantly. This has led to a steady rise in the number of infants born with neonatal opioid withdrawal syndrome (NOWS). Although short-term withdrawal symptoms associated with NOWS are well characterized, there are many gaps in our understanding of the short and long-term effects of prenatal opioid exposure. Current animal models of NOWS are limited by shortened gestational periods, large litter sizes, and primary organogenesis occurring after birth. This often leads to postnatal treatment to mimic drug exposure during third-trimester development. Using the unique rodent species Acomys cahirinus , more commonly known as spiny mice, which have an extended 40-day gestation period, small litter sizes, and increased in utero organogenesis we aim to study the short-term effects of prenatal morphine exposure by assessing withdrawal behavior. To model maternal opioid use, dams were treated daily with morphine (10 and 30 mg/kg S.C.) beginning on gestation day 19 until the day of birth; this resulted in a cumulative exposure of 19–21 days. Withdrawal behaviors for each pup were recorded daily between postnatal days 0–7 (PND 0–7). Our study found that prenatal morphine exposure in spiny mice led to an increase in withdrawal behavior throughout the early postnatal period and validated the use of this species as a novel pre-clinical model of NOWS. We are hopeful this rodent model will further our understanding of the short and long-term consequences of prenatal opioid exposure on neurodevelopment and behavior.

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The effect of pituitary adenylate cyclase-activating polypeptide on elevated plus maze behavior and hypothermia induced by morphine withdrawal

Cited by 8 publications

References 39 publications

Baclofen prevents the elevated plus maze behavior and BDNF expression during naloxone precipitated morphine withdrawal in male and female mice

Baclofen prevents the elevated plus maze behavior and BDNF expression during naloxone precipitated morphine withdrawal in male and female mice

Sex Differences in Behavioral and Brainstem Transcriptomic Neuroadaptations following Neonatal Opioid Exposure in Outbred Mice

Opioid withdrawal behavior in spiny mice: A novel preclinical model of neonatal opioid withdrawal syndrome (NOWS)

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