The suppressive effect of 1.0 mg/kg buprenorphine on IFN-g production is attenuated by administration of the opioid receptor antagonist, naltrexone.

1
The suppressive effect of 1.0 mg/kg buprenorphine
on IFN-g production is attenuated by
administration of the opioid receptor antagonist,
naltrexone. K.A. Carrigan et al., Int
Immunopharmacol 2004, 4419-428
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2

• CD4 T lymphocytes are the primary cell target
  for human immunodeficiency virus-1 (HIV-1), and
  these cells are known to express opioid
  receptors.
• Due to the need for new treatment approaches to
  HIV-1 infection, we sought to determine whether
  the non-selective opioid receptor antagonist
  naltrexone would affect HIV-1 expression in CD4
  lymphocyte cultures and whether naltrexone would
  alter the antiviral properties of zidovudine
  (AZT) or indinavir.
• Activated CD4 lymphocytes were infected with a
  monocytotropic or T-cell tropic HIV-1 isolate,
  and p24 antigen levels were measured in
  supernatants of drug-treated or untreated
  (control) cultures.
• While naltrexone alone did not affect HIV-1
  expression, at a concentration of 10-1210-10 M
  naltrexone increased the antiviral activity of
  AZT and indinavir 23-fold.
• Similar findings with a k-opioid receptor (KOR)
  selective antagonist supported the possible
  involvement of KOR in naltrexones potentiation
  of the antiretroviral drugs.
• The results of this in vitro study suggest that
  treatment of alcohol or opiate dependent
  HIV-1-infected patients with naltrexone is
  unlikely to interfere with the activity of
  antiretroviral drugs. Also, based upon
  naltrexones safety profile and its synergistic
  activity in vitro, these findings suggest
  clinical trials should be considered of
  naltrexone as an adjunctive therapy of HIV-1
  infection.

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3
The analgesic property of opiates has been known
since ancient times. Only recently has an
appreciation of the broad effects of opioids on
the inflammatory response emerged. Acting largely
through m-, k- and d-opioid G protein-coupled
receptors on T lymphocytes and macrophages,
cognate ligands modulate many activities of these
cells, including cytokine production. In addition
to acting as chemotactic stimuli, opioids can,
through the process of heterologous
cross-desensitization, act as stop signals in
leukocyte trafficking. When administered into the
central nervous system, certain chemokines can
cross-desensitize to the analgesic effect of
opioids. We propose that opioids should be
considered members of the cytokine family and
that future research on opioids could yield new
therapies for inflammatory and infectious
diseases, including HIV-1 infection.
We propose that opioids should be considered
members of the cytokine family and that future
research on opioids could yield new therapies for
inflammatory and infectious diseases, including
HIV-1 infection.
2
4
Opioid and chemokine receptor expression by T
cells, monocytes, microglial cells and neurons.
Neuronmicroglial cell communication occurs
through the release of various chemical
mediators, including the production of CX3CL1
(fractalkine) by neurons and the production of
additional chemokines, such as CCL3, CCL4 and
CCL5, by microglial cells.
The chemokines produced by microglial cells (and
astrocytes) in the brain act as chemoattractants
and/or activators of circulating T cells and
monocytes. The production of CCL2 is a potent
chemoattractant for the passage of monocytes
through the bloodbrain barrier. In addition,
endogenous opioids, produced in the brain and by
cells of the immune system, act to regulate
circulating immune cells and microglial-cell
inflammatory activities.
3
5
Model describing the influence of opioids on HIV
replication. MOR activation of macrophages and
potentially T cells and microglia initiates an
increase in the expression of chemokines CCL2,
CCL5 and CXCL10, which might act to attract
susceptible T cells, monocytes and/or macrophages
or microglia to the site of HIV infection.
m-opioid receptor (MOR) ligands also signal an
upregulation in the expression of the major HIV
coreceptors CCR5 and CXCR4. By contrast, k-opioid
receptor (KOR) activation directly (and probably
indirectly) inhibits the expression of
proinflammatory cytokines and chemokines. This
results in a depressed state of cellular
activation and reduced HIV replication. In
addition, KOR signals an inhibition of the
expression of CCR5 and CXCR4, leading to reduced
HIV binding and reduced chemotaxis of potentially
susceptible target cells.
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6
m-Opioid modulation of HIV-1 coreceptor
expression and HIV-1 replication Steele A.D, et
al., 3099910 (2003)
A substantial proportion of HIV-1-infected
individuals are intravenous drug users (IVDUs)
who abuse opiates. Opioids induce a number of
immunomodulatory effects that may directly
influence HIV-1 disease progression. In the
present report, we have investigated the effect
of opioids on the expression of the major HIV-1
coreceptors CXCR4 and CCR5. For these studies we
have focused on opiates which are ligands for the
m-opioid receptor. Our results show that DAMGO, a
selective m-opioid agonist, increases CXCR4 and
CCR5 expression in both CD3 lymphoblasts and
CD14 monocytes three- to fivefold. Furthermore,
DAMGO-induced elevation of HIV-1 coreceptor
expression translates into enhanced replication
of both X4 and R5 viral strains of HIV-1. We have
confirmed the role of the mopioid receptor based
on the ability of a m-opioid receptor-selective
antagonist to block the effects of DAMGO. We have
also found that morphine enhances CXCR4 and CCR5
expression and subsequently increases both X4 and
R5 HIV-1 infection. We suggest that the capacity
of m-opioids to increase HIV-1 coreceptor
expression and replication may promote viral
binding, trafficking of HIV-1-infected cells, and
enhanced disease progression.
Our results show that DAMGO, a selective
m-opioid agonist, increases CXCR4 and CCR5
expression in both CD3 lymphoblasts and CD14
monocytes three- to fivefold. Furthermore,
DAMGO-induced elevation of HIV-1 coreceptor
expression translates into enhanced replication
of both X4 and R5 viral strains of HIV-1.
7
Low-dose naltrexone effects on plasma chemistries
and clinical symptoms in autism a double-blind,
placebo-controlled study
Bouvard M.P., et al.
The effect of month-long naltrexone (NTX)
treatment at a daily oral dose of 0.5 mg/kg/day
was contrasted with placebo (PLC) in a
double-blind study with conjoint clinical and
biochemical evaluations of therapeutic effects.
Modest clinical benefits were achieved with both
PLC and NTX, with marginally better overall
results following NTX, and degree of improvement
appeared to be related to plasma chemical
profiles. Massively elevated levels of
b-endorphin were observed in all children with
assays using C-terminal antibody but not with an
N-terminal antibody assay. In addition, 70 of
the children exhibited abnormally low levels of
adrenocorticotropic hormone, and smaller subsets
exhibited elevated norepinephrine (6_at_),
arginine-vasopressin (SO), and serotonin (20).
The best clinical responders exhibited the
clearest normalization of the elevated plasma
chemistries, especially in C-terminal-endorphin
and serotonin. There was some evidence of
therapeutic carry-over effects in both clinical
and biochemical measures in those children who
received NTX before PLC. The results suggest that
NTX only benefits a subgroup of autistic
children, who may be identified by the presence
of certain plasma abnormalities. These results
suggest a possible linkage between abnormal
plasma chemistries, especially those related to
the pro-opiomelanocortin system, and autistic
symptoms.
The results suggest that NTX only benefits a
subgroup of autistic children, who may be
identified by the presence of certain plasma
abnormalities. These results suggest a possible
linkage between abnormal plasma chemistries,
especially those related to the
pro-opiomelanocortin system, and autistic
symptoms.
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Smith J.P., et al., 102820828, 2007
Low-Dose Naltrexone Therapy Improves Active
Crohns Disease

• STUDY HIGHLIGHTS
• What Is Current Knowledge
• The current medical therapy of Crohns disease
  includes medications that target the immune
  system or inflammatory modulators.
• Opioid systems (peptides and receptors) play an
  integral role in gastrointestinal fluid
  regulation, pain perception, and inflammation.
• Many of the current drugs for treatment of
  Crohns disease carry a greater risk of infection
  from immunosuppression or allergic reactions, and
  some must be administered parenterally.
• What Is New Here
• An opioid antagonist, naltrexone 4.5 mg,
  administered by mouth once daily significantly
  improved Crohns disease activity index (CDAI)
  scores and symptoms in subjects with active
  Crohns disease.
• Quality of life significantly improved with
  low-dose naltrexone therapy and remained improved
  after discontinuation of the drug.
• Naltrexone therapy was well tolerated in Crohns
  disease with minimal side effects.

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Low-dose naltrexone therapy in multiple sclerosis
Agrawal Y.P.
The use of low doses of naltrexone for the
treatment of multiple sclerosis (MS) enjoys a
worldwide following amongst MS patients. There is
overwhelming anecdotal evidence, that in low
doses naltrexone not only prevents relapses in MS
but also reduces the progression of the disease.
It is proposed that naltrexone acts by reducing
apoptosis of oligodendrocytes. It does this by
reducing inducible nitric oxide synthase
activity. This results in a decrease in the
formation of peroxynitrites, which in turn
prevent the inhibition of the glutamate
transporters. Thus, the excitatory neurotoxicity
of glutamate on neuronal cells and
oligodendrocytes via activation of the a-amino-3-
hydroxy-5-methyl-isoxazole-4-propionic acid class
of glutamate receptor is prevented. It is crucial
that the medical community respond to patient
needs and investigate this drug in a clinical
trial.
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10
Antibodies to Neuron-Specific Antigens in
Children with Autism Possible Cross-Reaction
with Encephalitogenic Proteins from Milk,
Chlamydia pneumoniae and Streptococcus Group
AJournal of Neuroimmunology, 129168-177 2002 A.
Vojdani, A.W. Campbell, E. Anyanwu, A. Kashanian,
K. Bock, E. Vojdani
Infections, Toxic Chemicals and Dietary Peptides
Binding to Lymphocyte Receptors and Tissue
Enzymes are Major Instigators of Autoimmunity in
Autism Int J Immunopathol Pharmacol
16(3)189-199, 2003 A. Vojdani, J.B. Pangborn, E.
Vojdani, E.L.Cooper
Heat Shock Protein and Gliadin Peptide Promote
Development of Peptidase Antibodies in Children
with Autism and Patients with Autoimmune Disease
Clin Diag Lab Immunol 11(3)515-524, 2004 A.
Vojdani, M. Bazargan, E. Vojdani, J. Samadi, A.A.
Nourian, N. Eghbalieh, E.L. Cooper
Immune Response to Dietary Proteins, Gliadin and
Cerebellar Peptides in Children with
AutismNutritional Neuroscience, 7(3)151-161,
2004 Vojdani, T. OBryan, J.A. Green, J.
McCandless, K.N. Woeller, E. Vojdani, A.A.
Nourian, E.L. Cooper
Antibodies against Central Nervous System
Antigens in Autism Possible Cross-Reaction with
Dietary Proteins and Infectious Agent
Antigens.Neuropsychiatric Disorders
Infections, pp 171-186, 2005, S.H. Fatemi (ed),
Taylor Francis Ltd Vojdani, T. OBryan, J.A.
Green, J. McCandless, K.N. Woeller, E. Vojdani,
A.A. Nourian, E.L. Cooper
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11
journal of
Neuroimmunology
Journal of Neuroimmunology (In Press)
Low natural killer cell cytotoxic activity in
autism the role of glutathione, IL-2 and
IL-15 A. Vojdani, et al. Although many
articles have reported immune abnormalities in
autism, NK cell activity has only been examined
in one study of 31 patients, of whom 12 were
found to have reduced NK activity. The mechanism
behind this low NK cell activity was not
explored. For this reason, we explored the
measurement of NK cell activity in 1027 blood
samples from autistic children obtained from ten
clinics and compared the results to 113 healthy
controls. This counting of NK cells and the
measurement of their lytic activity enabled us to
express the NK cell activity/100 cells. At the
cutoff of 15-50 LU we found that NK cell activity
was low in 41-81 of the patients from the
different clinics. This NK cell activity below 15
LU was found in only 8 of healthy subjects (p lt
0.001). Low NK cell activity in both groups did
not correlate with percentage and absolute number
of CD16/CD56 cells. When the NK cytotoxic
activity was expressed based on activity/100
CD16/CD56 cells, several patients who had
displayed NK cell activity below 15 LU exhibited
normal NK cell activity. Overall, after this
correction factor, 45 of the children with
autism still exhibited low NK cell activity,
correlating with the intracellular level of
glutathione. Finally, we cultured lymphocytes of
patients with low or high NK cell activity/cell
with or without glutathione, IL-2 and IL-15. The
induction of NK cell activity by IL-2, IL-15 and
glutathione was more pronounced in a subgroup
with very low NK cell activity. We conclude that
45 of a subgroup of children with autism suffers
from low NK cell activity, and that low
intracellular levels of glutathione, IL-2 and
IL-15 may be responsible.
The induction of NK cell activity by IL-2, IL-15
and glutathione was more pronounced in a subgroup
with very low NK cell activity. We conclude that
45 of a subgroup of children with autism suffers
from low NK cell activity, and that low
intracellular levels of glutathione, IL-2 and
IL-15 may be responsible.
12
Percentage of NK cell activity below 15 lytic
units in controls and patients with autism
obtained from 10 different clinics. Vojdani A.
et al., Journal of Neuroimmunology 2008 (In Press)
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Effects of Opioids on the Immune System
Schematic representation of the hematopoietic
system showing the differentiation pathways
sensitive to opioids. from Effects of Opioids on
the Immune System Roy S. and Loh H.H.,
Neurochemical Research, 211375-1386, 1996
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NALTREXONE
High Dose
Low Dose
d-Opioid Receptor Antagonist
d-Opioid Receptor Agonist

• Stimulation of
• T, B and NK function
• IFN-g and IL-2 production

• Inhibition of
• T, B and NK function
• IFN-g and IL-2 production

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MECHANISM OF ACTION OF LDN
LDN
Regulation of TReg and production of IL-10 and
TGF-b
Blockade of opiate-R in GI tract
Interaction of the nuclear opioid growth factor
receptor
Inhibition of proinflammatory cytokines
Increase in endogenous enkephalin and endorphin
Effect on no. of liquid bowel movements
Promotion Of DNA synthesis
Healing repair of mucosal tissue
Improvement in Crohns disease activity
Healing of corneal ulcers
Improvement in inflammatory reaction
Enhancement of immune function
Down regulation of TH-17
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The Role of Environmental Factors in Gut-Brain
Inflammation and Its Possible Inhibition by LDN
LDN
LDN
LDN
LDN
LDN
LDN
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