| Abstract |
Opioids are pluripotent agents, involved in a number of key actions, including
antinociception, immunomodulation, inhibition of cancer cell growth and modulation of
the motility of normal and cancer cells. The aim of the present study was to investigate
opioid effects on two significant functions of the immune system: constitutive secretion
and cell motility.
Our results show that opioids decrease antibody and cytokine secretion by both multiple
myeloma cell lines (LP-1 and RPMI8226) and normal B lymphocytes (CD19+) and
inhibit their growth. On the contrary, secretion of IgE and IL-6 by U266 cells was
increased, while their proliferation was also inhibited. Our data present for the first time
two different mechanisms of opioid action on B-cells: an early, non-opioid receptorrelated
mechanism, controlling antibody and cytokine secretion, and a receptormediated
long-term action on cell growth. The first mechanism, involves JNK/c-Jun
and/or p38/CREB to modulate secretion, while the second mechanism, involving opioid
receptors, is mediated through PI3k/Akt inhibition to suppress cell proliferation. Both
mechanisms relay the opioid system (circulating or locally produced opioids) in
humoral immunity regulation. These data provide some additional information
concerning opioid effects on B-cells, which until recently, are reported to be indirect,
through the modulation of humoral agents secreted by other immune cells and interplay
of distinct cell populations (e.g T-cells, macrophages). Further identification and
characterization of signal transduction pathways responsible for these unique properties
of opioids may represent major research challenge ahead.
The study of lymphocyte migration in vitro is rather complicated, due to the need of cocultures
of different cell systems. Therefore, we examined the effects of opioids on
migration of cancer cells instead, since most structural and regulatory molecules used in
the migratory process seem to be similar among migrating cells. Furthermore, the
investigation of opioid effects on cancer cell migration may provide further information
on their metastatic properties, as cell migration is a prerequisite for cancer metastasis.
In order to examine opioid actions on cell motility, we used cancer cells of different
origin (bladder, liver, cervix, ovary and breast). Our results showed that morphine has
little effect on the metastatic properties (migration, adhesion and spreading on collagen
type I) of hepatocyte (HepG2) and cervical (HeLa) cancer cells, while has not effect on
breast (MCF-7) and ovarian cancer cells (SKOV-3). On the contrary, all opioids used,
enhanced the metastatic properties of bladder cancer cells (T24 και EJ). Furthermore,
they induced invasiveness of these cells through ECM components, increased secretion
of MMP-2 and -9 and induced rearrangements of filamentous actin cytoskeleton. These
actions were mediated by p38, ERK 1/2, PI3k and -to a lesser degree- JNK activation
through a non-opioid receptor related manner. Moreover, a novel interaction of opioids
with bradykinin B2 receptor was characterized, mediating opioid effects on bladder
cancer cell migration, suggesting a new role of opioids in the cancer process.
Τhe present study provides new evidence about the direct actions of opioids on antibody
secretion by B lymphocytes and their role in cell migration. Further investigation is
needed in order to elucidate the mechanisms of action of opioids controlling secretion
and migration of the immune cells, thus leading to a better understanding of their role as
immunomodulatory agents. Furthermore, our data shed light on a non well documented
action of opioids, their role in cancer metastasis since the existing literature is
inconclusive.
In conclusion, our findings connect stress-related substances such as opioids with
immunity and neoplasia. Given the fact that opioids are mainly secreted from and act on
the CNS, our results have possible applications on neurodegenerative diseases and CNS
neoplasias. Indeed, the association between B-lymphocytes and the progression of
neurodegenerative diseases (e.g. multiple sclerosis) is now evident. In combination with
our results, the involvement of opioids on B-lymphocytes functions provides the
theoretical basis for the control of opioid contribution to the progress of
neurodegenerative diseases. Furthermore, since cancer metastasis can be affected by
opioids, the elucidation of the role of the latter as possible regulatory factors of CNS
malignancies is essential. Finally, our findings explain the decreased humoral immunity
of patients treated with opioids or in cases of opioid abuse.
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