Cultured murine bone marrow macrophages specifically bound 125I-labeled β-endorphin. Binding was displaceable by 100 times molar excess of full-length β-endorphin but was insensitive to the opioid receptor antagonist, naloxone. Binding was inhibited by β-endorphin's C-terminal tetrapeptide, lys-lys-gly-glu, but not by the truncated N-terminal 27 amino acid fragment, indicating that binding of β-endorphin to this receptor is dependent on its C-terminus. Macrophages incubated for 24 h with 10 −8–10 −5 M prostaglandin E 2 showed a dose-dependent increase in β-endorphin binding, implying receptor up-regulation. This was also observed in response to the phosphodiesterase inhibitor, isobutylmethylxanthine, indicating that regulation of these receptors may be mediated through a cAMP-dependent process. This is the first demonstration that β-endorphin receptor expression can be positively regulated.