Long-term changes in reward-seeking following morphine withdrawal are associated with altered N-methyl-d-aspartate receptor 1 splice variants in the amygdala

Anderson, Ethan M.; Neubert, John K.; Caudle, Robert M.

doi:10.1016/j.neuroscience.2012.07.037

Cited by 11 publications

(7 citation statements)

References 54 publications

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“…Similar treatment in rat pups also impaired the adult cognitive functioning (McPherson et al, 2007) as demonstrated by (1) impaired passive avoidance learning (test classically used to assess learning and memory mediated by amygdala), (2) conditioned place preference (mediated by the mesolimbic dopamine system (Prus et al, 2009)), and (3) the forced swimming learning paradigms (which involve serotonergic system (Petit‐Demouliere et al, 2005)). Early life‐prolonged opioid exposure is also associated with long‐term effect such as: decreased analgesia, increased pain sensitivity (Zhang and Sweitzer, 2008), and hypersensitivity to adverse/stress conditions (Anderson et al, 2012). However, these studies did not investigate underlying cellular neuroplasticity that might explain reported behavioral changes.…”

Section: Discussionmentioning

confidence: 99%

Morphine‐enhanced apoptosis in selective brain regions of neonatal rats

Bajic

Commons

Soriano

2013

Intl J of Devlp Neuroscience

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Prolonged neonatal opioid exposure has been associated with: antinociceptive tolerance, long-term neurodevelopmental delay, cognitive, and motor impairment. Morphine has also been shown to induce apoptotic cell death in vitro studies, but its in-vivo effect in developing rat brain is unknown. Thus, we hypothesized that prolongued morphine administration in neonatal rats in a model of antinociceptive tolerance and dependence is associated with increased neuroapoptosis. We analyzed neonatal rats from the following groups (1) naïve group (n=6); (2) control group (normal saline (NS), n=5), and (3) morphine group (n=8). Morphine sulfate or equal volume of NS was injected subcutaneously twice daily for 6.5 days starting on postnatal day (PD) 1. Development of antinociceptive tolerance was confirmed by Hot Plate test on the 7th day. Evidence of neuronal and glial apoptosis was determined by cleaved caspase-3immunofluorescence combined with specific markers. At PD7, morphine administration after 6 ½ days significantly increased the density of apoptotic cells in the cortex and amygdala, but not in the hippocampus, hypothalamus, or periaqueductal gray. Apoptotic cells exhibited morphology analogous to neurons. Irrespective of the treatment, only a very few individual microglia but not astrocytes were caspase-3 positive. In summary, repeated morphine administration in neonatal rats (PD1-7) is associated with increased supraspinal apoptosis in distinct anatomical regions known to be important for sensory (cortex) and emotional memory processing (amygdala). Brain regions important for learning (hippocampus), and autonomic and nociceptive processing (hypothalamus and periaqueductal gray) were not affected. Lack of widespread glial apoptosis or robust glial activation following repeated morphine administration suggests that glia might not be affected by chronic morphine at this early age. Future studies should investigate long-term behavioral sequelae of demonstrated enhanced apoptosis associated with prolonged morphine administration in a neonatal rat model.

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Section: Discussionmentioning

confidence: 99%

Morphine‐enhanced apoptosis in selective brain regions of neonatal rats

Bajic

Commons

Soriano

2013

Intl J of Devlp Neuroscience

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“…Reports of increased pain sensitivity [39], altered anxiety and stress responses, metabolic changes [40], and potential memory changes (through amygdalo-frontal circuits) [11] have also been reported. These changes may also reflect an overall hypersensitivity and maladaptation to adverse conditions [41] in premature infants. It is however, well established that prematurity alone is associated with numerous neurological sequelae [42], including high risk for cerebral injuries such as hypoxia–ischemia events, stroke, and periventricular leukomalacia [43] implicating prematurity as a significant confounding factor in evaluating neurodevelopment.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of Postnatal Sedation in Full-Term Infants

2019

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Prolonged sedation in infants leads to a high incidence of physical dependence. We inquired: (1) “How long does it take to develop physical dependence to sedation in previously naïve full-term infants without known history of neurologic impairment?” and (2) “What is the relationship between length of sedation to length of weaning and hospital stay?”. The retrospective study included full-term patients over a period of one year that were <1 year of age and received opioids and benzodiazepines >72 hours. Quantification of fentanyl, morphine, and midazolam were compared among three time periods: <5 days, 5–30 days, and >30 days using t-test or one-way analysis of variance. Identified full-term infants were categorized into surgical (14/44) or medical (10/44) groups, while those with neurological involvement (20/44) were excluded. Physical dependence in full-term infants occurred following sedation ≥5 days. Infants with surgical disease received escalating doses of morphine and midazolam when administered >30 days. A positive association between length of sedation and weaning period was found for both respiratory (p < 0.01) and surgical disease (p = 0.012) groups, while length of sedation is related to hospital stay for the respiratory (p < 0.01) but not the surgical disease group (p = 0.1). Future pharmacological directions should lead to standardized sedation protocols and evaluate patient neurocognitive outcomes.

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“…An example of the data collected is presented in Figure 1C . The use of the OPAD assay has been described extensively in our previous publications ( Neubert et al, 2005 ; Neubert et al, 2006 ; Neubert et al, 2007 ; Neubert et al, 2008 ; Rossi and Neubert, 2008 ; Rossi et al, 2009 ; Caudle et al, 2010 ; Kumada et al, 2012 ; Nolan et al, 2011 ; Anderson et al, 2012a ; Anderson et al, 2012b ; Nolan et al, 2012 ; Ramirez and Neubert, 2012 ; Rossi et al, 2012 ; Anderson et al, 2013 ; Mustafa et al, 2013 ; Anderson et al, 2014 ; Anderson et al, 2015 ; Ramirez et al, 2015 ; Bowden et al, 2017 ; Caudle et al, 2017 ).…”

Section: Methodsmentioning

confidence: 99%

Pharmacological Characterization of Orofacial Nociception in Female Rats Following Nitroglycerin Administration

Caudle

Flenor

et al. 2020

Front. Pharmacol.

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Rodent models of human disease can be valuable for understanding the mechanisms of a disease and for identifying novel therapies. However, it is critical that these models be vetted prior to committing resources to developing novel therapeutics. Failure to confirm the model can lead to significant losses in time and resources. One model used for migraine headache is to administer nitroglycerin to rodents. Nitroglycerin is known to produce migraine-like pain in humans and is presumed to do the same in rodents. It is not known, however, if the mechanism for nitroglycerin headaches involves the same pathological processes as migraine. In the absence of known mechanisms, it becomes imperative that the model not only translates into successful clinical trials but also successfully reverse translates by demonstrating efficacy of current therapeutics. In this study female rats were given nitroglycerin and nociception was evaluated in OPADs. Estrous was not monitored. Based on the ED50 of nitroglycerin a dose of 10 mg/kg was used for experiments. Sumatriptan, caffeine, buprenorphine and morphine were administered to evaluate the reverse translatability of the model. We found that nitroglycerin did not produce mechanical allodynia in the face of the rats, which is reported to be a consequence of migraine in humans. Nitroglycerin reduced the animals’ participation in the assay. The reduced activity was verified using an assay to measure exploratory behavior. Furthermore, the effects of nitroglycerin were not reversed or prevented by agents that are effective acute therapies for migraine. Two interesting findings from this study, however, were that morphine and nitroglycerin interact to increase the rats’ tolerance of mechanical stimuli on their faces, and they work in concert to slow down the central motor pattern generator for licking on the reward bottle. These interactions suggest that nitroglycerin generated nitric oxide and mu opioid receptors interact with the same neuronal circuits in an additive manner. The interaction of nitroglycerin and morphine on sensory and motor circuits deserves additional examination. In conclusion, based on the results of this study the use of nitroglycerin at these doses in naïve female rats is not recommended as a model for migraine headaches.

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Long-term changes in reward-seeking following morphine withdrawal are associated with altered N-methyl-d-aspartate receptor 1 splice variants in the amygdala

Cited by 11 publications

References 54 publications

Morphine‐enhanced apoptosis in selective brain regions of neonatal rats

Morphine‐enhanced apoptosis in selective brain regions of neonatal rats

Evaluation of Postnatal Sedation in Full-Term Infants

Pharmacological Characterization of Orofacial Nociception in Female Rats Following Nitroglycerin Administration

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