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Published on: April 29, 2015
Altered subcellular signaling in murine peritoneal macrophages upon chronic morphine exposure
Ana M Lugo-Chinchilla1, Dennise Báez, Mariella Vélez
1Department of Natural Sciences, Interamerican University, Bayamón Campus, Bayamón, Puerto Rico.
Abstract:
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is causally related to inhibition of phagocytosis since an artificial increase in cAMP inhibits phagocytosis in non-withdrawn cells exposed chronically to morphine.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.
Insights
Opioid exposure alters macrophage function. Acute morphine inhibits phagocytosis via a pertussis toxin-sensitive pathway, while withdrawal increases cAMP and impairs phagocytosis through a different mechanism.
Area of Science:
- Immunology
- Neuroscience
- Pharmacology
Background:
- Opioid signaling in immune cells is complex and not fully understood.
- Macrophages play a crucial role in immune responses, including phagocytosis.
- Opioid exposure can modulate immune cell function, impacting host defense.
Purpose of the Study:
- To investigate the effects of acute and chronic morphine exposure on murine peritoneal macrophage function.
- To elucidate the signaling pathways involved in morphine-induced alterations of phagocytosis and cAMP levels.
- To understand the mechanisms underlying morphine tolerance and withdrawal in macrophages.
Main Methods:
- Murine peritoneal macrophages were exposed to morphine acutely and chronically in vitro.
- Fc-mediated phagocytosis assays were performed to assess macrophage function.
- Cyclic adenosine monophosphate (cAMP) levels were measured.
- Pertussis toxin (PT) sensitivity was evaluated to determine signaling pathways.
Main Results:
- Acute morphine exposure inhibited Fc-mediated phagocytosis via a PT-sensitive pathway without affecting cAMP.
- Chronic morphine exposure led to tolerance, with equivalent phagocytosis and cAMP levels.
- Morphine withdrawal after chronic exposure inhibited phagocytosis and increased cAMP 4-fold via a PT-insensitive mechanism.
- Elevated cAMP levels were causally linked to phagocytosis inhibition.
Conclusions:
- Macrophage opioid receptor signaling shifts depending on the exposure conditions.
- Acute exposure involves a Gi/o-mediated pathway not involving adenylate cyclase.
- Chronic exposure and withdrawal involve non-Gi/o-mediated adenylate cyclase superactivation, impacting phagocytosis.
