Altered subcellular signaling in murine peritoneal macrophages upon chronic morphine exposure

Alterations in opioid signaling that take place in murine peritoneal macrophages in vitro are variably dependent on opiate exposure conditions. Acute exposure to morphine inhibits Fc-mediated phagocytosis by a pertussis toxin (PT)-sensitive mechanism, but has no effect on cAMP levels. In contrast, chronic exposure to morphine results in a “tolerant” state, wherein test and control values for both phagocytosis and cAMP are equivalent. However, drug withdrawal after chronic exposure to morphine results in inhibition of phagocytosis and a concomitant 4-fold increase in cAMP by a PT-insensitive mechanism. This increase is causally related to inhibition of phagocytosis since an artificial increase in cAMP inhibits phagocytosis in non-withdrawn cells exposed chronically to morphine. We suggest that macrophage opioid receptors signaling switches from a Gi/o-mediated mechanism that does not involve adenylate cyclase in acute exposure to a non-Gi/o-mediated adenylate cyclase superactivation during chronic exposure.