INDUCTION OF OPIOID RECEPTOR-MEDIATED MACROPHAGE CHEMOTACTIC ACTIVITYAFTER 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 co rtex 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 fac tor (BDCF) capable of eliciting chemotactic responses from resident pe ritoneal macrophages and brain macrophages. Conditioned media collecte d 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 recepto r antagonist, completely blocks BDCF activity. Although both kappa and mu opioid receptor antagonists failed to modify BDCF-induced macropha ge chemotaxis, two specific delta receptor antagonists blocked BDCF. A nalysis of BDCF by reverse phase HPLC and RIA revealed peak chemotacti c activity in fractions consistent with the presence of an opioid pept ide. The results suggest that cells in the brain respond to neuronal i njury by producing and releasing opioids that can initiate a specific macrophage response.