Download Opioids and the immune system.

“I would have everie man write what he knows and no more.”—MONTAIGNE
BRITISH JOURNAL OF ANAESTHESIA
VOLUME 81, NO. 6
DECEMBER 1998
EDITORIAL
Opioids and the immune system
There has been growing interest in the significance of
neuropeptides in the immune system which has
resulted in the recent publication of an editorial1 and
review2 which are deserving of interest within the
anaesthetic community. There is now a considerable
body of literature which demonstrates a modulatory
function of the immune system by opioids. This
modulation takes the form of an alteration in the biochemical and proliferative properties of the various
cellular components of the immune system. As many
of the mechanisms and molecules are almost identical within vertebrates and invertebrates, it would
seem that opioid peptide immunoregulatory mechanisms first evolved in primitive organisms. Because
they have been conserved, it would suggest that this
remains a highly significant mechanism in humans.
Opioid precursors have been isolated and
sequenced from a variety of invertebrate species
(most work has been performed in the leech and
marine mussel) and these have a very close sequence
homology with the mammalian counterpart molecules. For instance, there is a 119 amino acid prodynorphin-like molecule which has an identical
number of [Leu]enkephalin sequences to that of
mammals. The leech has been shown to produce a
mammalian-like pro-opiomelanocortin (POMC)
molecule, and six of its peptides, including adrenocorticotropin (ACTH), a-melanocyte-stimulating
hormone (a-MSH) and [Met]enkephalin. The
proenkephalins from the leech and marine mussel
possess [Met] and [Leu]enkephalins with relevant
cleavage sites. In addition, opioid binding experiments have shown that delta 1 and delta 2 opioid
receptor subtypes (in common with those in
humans) are present in leech ganglia and immunocytes, and mussel immunocytes.3
Vertebrates and invertebrates have been shown to
possess a peptide which is a proenkephalin and has a
strong antibacterial action.4 This peptide is called
enkelytin (proenkephalin-A) and there is a strong
sequence homology between invertebrate and mammalian enkelytin.5 The presence of this strongly
antibacterial enkelytin further strengthens the association between opioid peptides and the immune system. It has been suggested that immune or neural
signalling leads to enhanced proenkephalin proteolytic cleaving thereby causing the release of both
opioid peptides and enkelytin simultaneously. This
scenario would allow a two-pronged attack. Opioid
peptides would modulate neutrophil chemotaxis,
phagocytic activity and the secretion of cytokines,
while the simultaneously liberated enkelytin would
exert an antibacterial action.
Because of the involvement of the peripheral and
central nervous systems with immune function it
now becomes feasible to consider the link between
pain and the immune system. A unified response to a
painful stimulus which would include a sensing
mechanism providing an initial avoidance response,
together with a later local analgesic response in the
tissues from endogenous opioids,6 and which is
associated with the release of potent antibacterial
peptides,5 is an ideal scenario. A similar pattern may
exist in humans.7
Corticotropin releasing hormone (CRH) is an
important hormone released under stress conditions
from both the hypothalamus and cells of the immune
system. Injection of CRH has been shown to produce
analgesia when injected into sites of local inflammation, an effect which is blocked by co-injection of
antiserum to ␤-endorphin.8 This again suggests a
possible mechanism whereby local activation of the
endogenous opioid system from immunocompetent
cells provides both an analgesic action and
anti-inflammatory effect.
Further evidence for the role of immune cells in
pain control pathways comes from work in rats following injection of antigen to induce inflammation in
a paw. Concentrations of ␤-endorphin were found to
increase in peripheral tissues while concentrations in
the lymph nodes which were previously high,
decreased.9 It is suggested that T lymphocytes may
be acting as vectors for ␤-endorphin to inflamed
tissues. The significance of this hypothesis is that it
would allow the potential for highly specific opioid
control of peripheral analgesia by targeted delivery of
␤-endorphin directly to sites of inflammation. This
would maximize the potential analgesic and antiinflammatory effects of endogenous opioids acting at
peripheral receptors and also by inhibiting the
release of the inflammatory peptide substance P from
primary afferent neurones.10
It is also possible that opioids released from cells of
the immune system may modulate release of
cytokines from the same and other cells of the
immune system.11 Beta-endorphin, [Met]enkephalin
and [Leu]enkephalin have been shown to inhibit the
secretion of the pro-inflammatory cytokine interleukin-6 (IL-6) from mouse spleen.12 Also, IL-6
production from activated peripheral blood
mononuclear cells is decreased by opioid peptides.13
On the other hand, cytokines have been shown to
regulate opioid formation in neural tissue culture
experiments. Interleukin-1␤ increases ␮ opioid receptor mRNA in cultured rat astrocytes and decreases
proenkephalin mRNA in hippocampal cultures.14 15
Proenkephalin mRNA and proenkephalin derived
peptides have been reported in human lymphocytes,
monocytes and macrophages. [Met]enkephalin is
released by human peripheral blood lymphocytes
which have been activated by phytohaemagglutinin.
Experiments using a blocking antibody to enkephalin
836
British Journal of Anaesthesia
demonstrated decreased DNA synthesis in stimulated human lymphocytes.16 However, others have
shown that delta opioid receptor agonists dose
dependently inhibit the proliferation of cultured
CD4+ and CD8+ T-cells from mice.18 A study using
specific ␮, ␦ and ␬ opioid receptor agonists have
shown that they result in significantly decreased
immunoglobulin production by activated human B
lymphocytes.13 Perhaps these different results are
caused by the effect of different cell types, different
species studied or because of the differing effects of
the various receptor subtypes.
In addition, there is much interest in the ability of
chronic opioid use to modify the immune system.
Much of this work stems from the observation that
parenteral drug abuse is a significant risk factor for
contracting human immunodeficiency virus type I
(HIV-1). Chronic morphine treatment is a mechanism used in laboratory experiments to render mice
immunocompromised.18 Morphine significantly
decreases in a dose dependent manner the proliferation of stimulated human lymphocytes in addition to
reducing the production of IFN-␣ and IFN-␤, an
effect reversed by naloxone.19 Gamma interferonstimulated natural killer cell cytotoxicity is significantly suppressed after short-term exposure to
morphine in humans.20
There is now a substantial body of evidence which
demonstrates that opioids and endogenous opioid
peptides modulate immune function. Moreover,
inflammatory mediators have been shown to modify
the release of opioid peptides from immune system
cells and also from cells of the peripheral and central
nervous system. The potential effects of exogenously
administered opioids on the immune system cannot
be ignored. Variations in postoperative infection rate
have not to date been attributed exclusively to the use
of perioperative opioids as there are many other compounding factors. However, it would seem most
likely that opioid use in both the surgical patient and
the critically ill would have a profound immunomodulatory effect and we should be cognizant of this
effect when we chose our anaesthetic, analgesic or
sedative technique.
N. R. WEBSTER
Anaesthesia and Intensive Care
Institute of Medical Sciences
Foresterhill
Aberdeen AB25 2ZD
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