Related Experiment Videos
Inhibitory effect of morphine on granulocyte stimulation by tumor necrosis factor and substance P
G B Stefano1, V Kushnerik, M Rodriquez
1Multidisciplinary Center for the Study of Aging, State University of New York College at Old Westbury, NY 11568.
Abstract:
We demonstrate that morphine, at higher concentrations than that effective in the inhibition of spontaneously active cells, can antagonize stimulation of human granulocytes by tumor necrosis factor (TNF) or substance P. The antagonistic effect appears to occur indirectly by way of downregulation of the cells' responsiveness to these stimulatory substances. We have previously shown that neutral endopeptidase 24.11 (NEP) is an important enzyme in neuro- and autoimmunoregulation of both vertebrates and invertebrates, and that activation of human granulocytes by monokines and neuropeptides results in regulation of NEP. Exposure of intact human granulocytes to morphine increases NEP by a naloxone-sensitive mechanism. The increased expression of NEP downregulates the stimulatory effect of substance P and TNF. In the case of substance P, we demonstrate the significance of NEP in modulating the process of downregulation by use of a specific NEP inhibitor, phosphoramidon. These results indicate that morphine is a significant factor in downregulating immunocyte responsiveness to NEP substrates and also to those signal molecules (i.e. cytokines) not metabolized by it. In summary, we infer that opiates may be endogenous signal molecules, a status that appears to be amply supported by their immunosuppressive actions.
Insights
Morphine antagonizes immune cell stimulation by downregulating responsiveness to substances like TNF. This involves increased neutral endopeptidase 24.11 (NEP) activity, suggesting opiates may act as endogenous immunosuppressive molecules.
Area of Science:
- Immunology
- Neuroscience
- Pharmacology
Background:
- Neutral endopeptidase 24.11 (NEP) plays a key role in neuro- and autoimmunoregulation.
- Activation of human granulocytes by monokines and neuropeptides modulates NEP activity.
- Morphine's effects on immune cells at higher concentrations are not fully understood.
Purpose of the Study:
- To investigate the antagonistic effect of morphine on human granulocyte stimulation by TNF and substance P.
- To elucidate the role of NEP in morphine-induced downregulation of immune cell responsiveness.
- To explore the potential of opiates as endogenous immunosuppressive signaling molecules.
Main Methods:
- Assessing the effect of morphine on human granulocyte stimulation by TNF and substance P.
- Measuring NEP expression in granulocytes following morphine exposure.
- Utilizing a specific NEP inhibitor (phosphoramidon) to study downregulation mechanisms.
Main Results:
- Morphine antagonizes TNF and substance P stimulation of human granulocytes at higher concentrations.
- Morphine increases NEP expression in granulocytes via a naloxone-sensitive pathway.
- Increased NEP activity downregulates the stimulatory effects of substance P and TNF on granulocytes.
Conclusions:
- Morphine significantly downregulates immunocyte responsiveness to NEP substrates and other signal molecules.
- Opiates may function as endogenous signaling molecules with immunosuppressive actions.
- NEP is a critical enzyme in mediating the immunosuppressive effects of morphine on immune cells.