Cell behavior and signal molecule involvement in a case study of malignant histiocytosis: A negative model of morphine as an immunoregulator

Abstract

In a patient diagnosed with histiocytic medullary reticulosis (HM), we examined immunocytes for their responsiveness towards known signaling molecules. Both the granulocytes and monocytes were found to exhibit a high level of spontaneous activation (96% compared to normal cells 7%; P < 0.001). These cells could not be downregulated when exposed to morphine. Following patient treatment with doxorubicin and cyclophosphamide, the immunocytes still exhibited a high spontaneous activation. They responded to morphine exposure in vitro with a cell rounding and becoming immobile for only 20 min whereas normal cells would remain round and immobile for up to 1-2 h. An examination of the plasma from the HM patient revealed that monocyte colony stimulating factor (MCSF) levels were elevated (6.4 and 5.78 compared to a control range of 1-1.75 ng/ml). In the HM patient, the immunocytes did not express the opiate selective and opioid peptide insensitive receptor, mu3, supporting the lack of opiate action. Given this finding, we incubated normal monocytes with MCSF and found that it significantly reduced the mu3 Bmax. Given the role of intracellular calcium in the activation process of immunocytes, we examined the action of various calcium channel blockers for their ability to inhibit the activated HM monocytes. The agents (nimodipine, cardiazem, and verapamil; 10[-9] M) were able to inhibit the HM-associated chemokinesis. Taken together, the data indicate that in the HM patient the immunocytes appear to be overactivated because stimulatory molecules are high and have the ability to downregulate the normal "braking" process. Additionally, the data indicate that MCSF deregulation may be involved as an initiating factor for this disorder.

Human White Blood Cells Synthesize Morphine: CYP2D6 Modulation

“…In addition to demonstrating the immunomodulating effect of morphine on PMN at the cellular level, our laboratory recently identified, using expression microarray analysis, that morphine altered expression of RNA in key pathways such as TNF signaling, IL-2 signaling, apoptosis, and oxidative stress response (44). Furthermore, in malignant histiocytosis, which is characterized by hyperactive immune cells, a condition that results in death, the 3 opiate receptor subtype was not expressed on human immunocytes, resulting in cells which could not be down-regulated by morphine (45). In general, morphine tended to down-regulate proinflammatory gene expression and up-regulate genes associated with signaling and immune down-regulation.…”

Endogenous morphine/nitric oxide-coupled regulation of cellular physiology and gene expression: Implications for cancer biology

“…Interestingly, we and others have shown that some human cancerous tissue contain morphine [152][153][154]. Furthermore, in medullary histolytic reticulosis, which is exemplified by cells having hyperactivity, an absence of μ 3 receptors, suggests a perturbation of morphine-regulated cellular events [155]. Thus, it would appear that morphinergic signaling has inserted itself in many processes taking a long time to evolve during evolution [148], including those regulating the proliferation of cells across diverse phyla.…”