Effects of neonatal stress and morphine on kappa opioid receptor signaling.
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.


OBJECTIVE
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.
Vien
Thuy N
TN
Department of Pediatrics, University of Washington, Seattle, WA 98195-6320, USA. sjuul@u.washington.edu
Gleason
Christine A
CA
Hays
Sarah L
SL
McPherson
Ronald J
RJ
Chavkin
Charles
C
Juul
Sandra E
SE
D000701:Analgesics, Opioid / Q000627:therapeutic use*; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D004745:Enkephalins / Q000502:physiology; D019085:Fluorescent Antibody Technique, Direct; D020868:Gene Silencing; D005904:Glial Fibrillary Acidic Protein; D005911:Gliosis / Q000139:chemically induced / Q000473:pathology; D005968:Glutamate Decarboxylase / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009020:Morphine / Q000627:therapeutic use*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D018384:Oxidative Stress; D011498:Protein Precursors / Q000502:physiology; D017473:Receptors, Opioid, kappa / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
D000701:Analgesics, Opioid; D004745:Enkephalins; D005904:Glial Fibrillary Acidic Protein; D009419:Nerve Tissue Proteins; D011498:Protein Precursors; D017473:Receptors, Opioid, kappa; C528900:glial fibrillary astrocytic protein, mouse; D009020:Morphine; C033660:preproenkephalin; D005968:Glutamate Decarboxylase