Effects of neonatal stress and morphine on kappa opioid receptor signaling
Thuy N Vien1, Christine A Gleason, Sarah L Hays
1Department of Pediatrics, University of Washington, Seattle, WA 98195-6320, USA. sjuul@u.washington.edu
Insights
Neonatal stress activates the kappa opioid receptor (KOR) system in mice, particularly when combined with morphine. This stress response involves the dynorphin system and can lead to inflammation in the brain.
Area of Science:
- Neuroscience
- Neonatal Research
- Pharmacology
Background:
- Critically ill neonates face significant stressors, often managed with opioids.
- Long-term effects of neonatal stress and opioid exposure remain unclear.
- The role of the kappa opioid system in neonatal stress is largely unknown.
Purpose of the Study:
- To map kappa opioid receptor (KOR) distribution in the neonatal mouse brain.
- To investigate how neonatal morphine, stress, or combined exposure alters KOR signaling.
Main Methods:
- Utilized wild-type and prodynorphin (Pdyn) knockout mouse models.
- Administered saline, morphine, or stress (with saline/morphine) from postnatal days 5-9.
- Examined brain tissue using KOR-P, GFAP, and GAD immunolabeling.
Main Results:
- Neonatal stress increased KOR-P in wild-type mice but not Pdyn(-/-) mice.
- Combined stress and morphine significantly elevated KOR-P (38-500%) and caused gliosis.
- Pdyn(-/-) mice showed increased gliosis even without KOR-P signaling.
Conclusions:
- Neonatal stress activates KOR through the dynorphin system.
- Co-exposure to stress and morphine exacerbates KOR activation and induces hippocampal gliosis.
- Endogenous dynorphin may mitigate stress-induced inflammatory responses.
Background:
Critically ill neonates experience multiple stressors during hospitalization. Opioids are commonly prescribed to ameliorate their pain and stress. However, the enduring effects of stress and opioids are not understood. The kappa opioid system is important in the mediation of stress in adults, but little is known about its function in neonates.
Objectives:
To characterize kappa opioid receptor (KOR) distribution in the neonatal mouse brain and test whether neonatal exposure to morphine, stress, or both, change KOR signaling.
Methods:
Five groups of wild-type C57BL/6 or prodynorphin (Pdyn) knockout mice were tested: (1) untreated control (dam-reared, no handling), (2) saline-injected control, (3) morphine-injected control, (4) stressed with saline injections and (5) stressed with morphine injections. Mice were treated from postnatal day 5 to postnatal day 9, after which their brains were immunolabeled with a phospho-specific KOR antibody (KOR-P), glial fibrillary acidic protein or glutamic acid decarboxylase.
Results:
There were no effects of saline or morphine injection on KOR-P immunoreactivity. Neonatal stress increased KOR-P labeling in wild-type brains (p < 0.05), but not in Pdyn(-/-) animals. Mice exposed to stress and morphine showed region-specific increases in KOR-P immunoreactivity from 38 to 500% (p < 0.05 to p < 0.001), with marked gliosis. In stressed morphine-treated Pdyn(-/-) animals, KOR-P immunoreactivity was absent, but gliosis increased compared to wild-type animals.
Conclusions:
Neonatal stress increases KOR activation via the dynorphin system. Neonatal stress plus morphine treatment further increased this response and also resulted in hippocampal gliosis. Enhanced gliosis noted in Pdyn(-/-) animals suggests that the endogenous dynorphin may play a role in downregulating this inflammatory response.
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