Induction of opioid receptor-mediated macrophage chemotactic activity after neonatal brain injury.
Macrophages have a prominent role in the injury response of the brain, yet the molecular mechanisms that control their invasion to the site of neuronal degeneration is unknown. After removal of the posterior cortex at birth, there is massive and specific targeting of nonresident macrophages to axotomized neurons in the lateral thalamus. The present study has identified an injury-induced, brain-derived chemotactic factor (BDCF) capable of eliciting chemotactic responses from resident peritoneal macrophages and brain macrophages. Conditioned media collected from tissue slices containing the axotomized central nervous system neurons exhibit BDCF activity. Initial experiments indicated that BDCF is a small peptide and, thus, we used specific pharmacologic reagents to characterize further BDCF activity. Naloxone, a pan opioid receptor antagonist, completely blocks BDCF activity. Although both kappa and mu opioid receptor antagonists failed to modify BDCF-induced macrophage chemotaxis, two specific delta receptor antagonists blocked BDCF. Analysis of BDCF by reverse phase HPLC and RIA revealed peak chemotactic activity in fractions consistent with the presence of an opioid peptide. The results suggest that cells in the brain respond to neuronal injury by producing and releasing opioids that can initiate a specific macrophage response.
Milligan
C E
CE
Department of Zoology, University of Massachusetts, Amherst 01003, USA.
Webster
L
L
Piros
E T
ET
Evans
C J
CJ
Cunningham
T J
TJ
Levitt
P
P
D000818:Animals; D000831:Animals, Newborn; D001930:Brain Injuries / Q000503:physiopathology*; D016923:Cell Death / Q000502:physiology; D002540:Cerebral Cortex / Q000293:injuries; D002630:Chemotactic Factors / Q000037:antagonists & inhibitors / Q000302:isolation & purification / Q000502:physiology; D002633:Chemotaxis / Q000502:physiology*; D005260:Female; D008264:Macrophages / Q000502:physiology*; D009410:Nerve Degeneration / Q000502:physiology; D018847:Opioid Peptides / Q000037:antagonists & inhibitors / Q000302:isolation & purification / Q000502:physiology; D011247:Pregnancy; D051381:Rats; D011957:Receptors, Opioid / Q000502:physiology*; D012995:Solubility; D013788:Thalamus / Q000378:metabolism
D002630:Chemotactic Factors; D018847:Opioid Peptides; D011957:Receptors, Opioid