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Science Forum Index » Immunology Forum » Low-dose naltrexone works for Crohn's; may affect cannabinoi
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| Kofi |
 Posted: Sat Jan 20, 2007 2:59 am |
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A new clinical trial indicates that low-dose naltrexone (LDN) is
effective for Crohn's disease [PMID 17222320]. I think this may be due
to the way friendly gut bacteria boost expression of mu opioid and
cannabinoid receptors and the way in which the two types of receptors
interact [PMID 16286810]. Gut dysbiosis is common with inflammatory
bowel problems and causes low mu opioid receptor expression [PMID
17159985]. Since LDN boost mu opioid receptor expression in a manner
similar to probiotics, this may be the reason - or at least a reason -
LDN works for Crohn's. It's doing a job that friendly bacteria can't.
Friendly gut bacteria found in yoghurt and probiotics (like
lactobacillus acidophilus) boost the synthesis of mu opioid and
cannabinoid receptors - natural painkillers - in human and rodent gut
cells. Rats given probiotics experienced a 20% increase in their pain
threshold or twice that if they already had irritable bowel syndrome.
The analgesic effect was similar to morphine and suggests the
microbiology of the intestinal tract influences our visceral pain
perception <http://www.newscientist.com/article/dn10808.html>, [PMID
17159985]. This may explain why so many people with gut dysbiosis
experience joint pain, TMJ, allodynia and so on.
Probiotics also inhibit allergies and, by guarding against leaky gut,
can block the initiation of autoimmunity. Their effects on neurological
receptors may be part of the way they accomplish this. For instance,
cannabinoids have effects on B cell production. Erasing friendly gut
bacteria might lower cannabinoid signaling enough to cause abnormal
antibody production - but that's my personal hypothesis.
Mu opioid receptors are downregulated by constant exposure to mu opioid
agonists like morphine or the natural opioid fragments from
partially-digested allergens passing through the gut barrier. I presume
patients chronically overexposed to antibiotics would only be all the
more likely to experience mu opioid downregulation. Mu opioid
expression might also drop with the sort of protein kinase C (PKC)
activation that accompanies zonulin signaling and the opening up of the
tight junction of the intestine. There's preliminary evidence PKC
somehow mediates morphine tolerance and downregulation of the mu opioid
receptor [PMID 17000011]. It may be the case that when LDN upregulates
mu opioid receptors, it's somehow interfering with PKC.
Zonulin is the "leaky gut" molecule that opens up the gut and exposes it
to immune cells [PMID 12654806, 12404235, 11193578, 10617135]. A number
of autoimmune conditions like type I diabetes get started with zonulin
signaling [PMID 16644703, 15710870]. Zonulin can be triggered by
infections or exposure to gluten/gliaden (only in Celiac disease does
the zonulin signaling persist for a long period of time) [PMID 12524403,
16635908, 16456012]. Zonulin's downstream signals are PKC and
phospholipase C (PLC). Blocking one of these signals might inhibit
leaky gut - and inducing one of them might make leaky gut more likely.
PKC is elevated by sugary foods/high blood glucose/insulin resistance,
homocysteine, and some drugs like minoxidil and morphine (when patients
develop tolerance/addiction). This may be why mixing antibiotics and a
sugary American diet leads to Candida problems and allergies. PKC is
downregulated/modulated by DHEA, omega-3 fish oils, carnitine and
ketogenic diets. Not so coincidentally, inflammatory bowel injuries
knock out carnitine transporters OCTN2 and Abt0+ [PMID 17065219,
15795384, 17142562, 16961737]; perhaps this carnitine loss elevates PKC
and makes leaky gut harder to stop. By no small coincidence, carnitine
also boosts the pain threshold and PKC inhibition boosts its effect
[PMID 15223307]. So LDN may also be partially making up for the loss of
carnitine uptake in inflamed intestines.
Given this association between mu opioid receptors and lactobacillus and
the benefit low-dose naltrexone has provided to Crohn's patients in this
trial, the next logical avenue to explore would be low-dose cannabinoid
antagonistss to restore downregulated cannabinoid receptors in the gut.
Unfortunately, this area has not been as well researched as the opioid
family. It appears as if cannabinoids have a connection with
autoimmunity. The loss of one or more cannabinoid receptor signals
could lead to B cell proliferation according to some of these papers.
In particular, deleting CB2 seems to cause an inflammatory bowel
condition in mice. The fact that CB2 is actually upregulated in I.B.D.
patients but absent in normal patients may indicate that the body is
trying to downregulate inflammation a little too late. Taking low-dose
CB1 or CB2 antagonists might boost receptor expression and enhance
sensitivity in the gut and local immune system to endogenous
cannabinoids and thus block B cell-led autoimmunity (but might also
leave you vulnerable to infection for the same reason rituxan does).
These are all educated guesses. I also don't know if this would produce
any psychoactive side effects. Straight CB1 agonists definitely do
that. To my knowledge, nobody's used low-dose antagonists in the
cannabinoid family like this before. Given the relatively recent
marketing of cannabinoid drugs like Rimonabant (a CB1 antagonist at
20mg) and cannabinol or cannabidiol (CB2 antagonists), I don't know how
easy it will be to compound these drugs into smaller doses.
___________________________________________
Am J Gastroenterol. 2007 Jan 11; [Epub ahead of print] Related Articles
Low-Dose Naltrexone Therapy Improves Active Crohn's Disease.
Smith JP, Stock H, Bingaman S, Mauger D, Rogosnitzky M, Zagon IS.
Department of Medicine, Pennsylvania State University College of
Medicine, Hershey, Pennsylvania, USA.
OBJECTIVES: Endogenous opioids and opioid antagonists have been shown to
play a role in healing and repair of tissues. In an open-labeled pilot
prospective trial, the safety and efficacy of low-dose naltrexone (LDN),
an opioid antagonist, were tested in patients with active Crohn's
disease. METHODS: Eligible subjects with histologically and
endoscopically confirmed active Crohn's disease activity index (CDAI)
score of 220-450 were enrolled in a study using 4.5 mg naltrexone/day.
Infliximab was not allowed for a minimum of 8 wk prior to study
initiation. Other therapy for Crohn's disease that was at a stable dose
for 4 wk prior to enrollment was continued at the same doses. Patients
completed the inflammatory bowel disease questionnaire (IBDQ) and the
short-form (SF-36) quality of life surveys and CDAI scores were assessed
pretreatment, every 4 wk on therapy and 4 wk after completion of the
study drug. Drug was administered by mouth each evening for a 12-wk
period. RESULTS: Seventeen patients with a mean CDAI score of 356 +/- 27
were enrolled. CDAI scores decreased significantly (P= 0.01) with LDN,
and remained lower than baseline 4 wk after completing therapy.
Eighty-nine percent of patients exhibited a response to therapy and 67%
achieved a remission (P < 0.001). Improvement was recorded in both
quality of life surveys with LDN compared with baseline. No laboratory
abnormalities were noted. The most common side effect was sleep
disturbances, occurring in seven patients. CONCLUSIONS: LDN therapy
appears effective and safe in subjects with active Crohn's disease.
Further studies are needed to explore the use of this compound. (Am J
Gastroenterol 2007;102:1-9).
PMID: 17222320 [PubMed - as supplied by publisher]
Behav Pharmacol. 2005 Dec;16( :597-603. Related Articles, Links
Ultra-low dose naltrexone enhances cannabinoid-induced antinociception.
Paquette J, Olmstead M.
Departments of aPsychology bPharmacology and Toxicology, Center for
Neuroscience Studies, Queen's University, Kingston, Ontario, Canada.
Both opioids and cannabinoids have inhibitory effects at micromolar
doses, which are mediated by activated receptors coupling to
Gi/o-proteins. Surprisingly, the analgesic effects of opioids are
enhanced by ultra-low doses (nanomolar to picomolar) of the opioid
antagonist, naltrexone. As opioid and cannabinoid systems interact, this
study investigated whether ultra-low dose naltrexone also influences
cannabinoid-induced antinociception. Separate groups of Long-Evans rats
were tested for antinociception following an injection of vehicle, a
sub-maximal dose of the cannabinoid agonist WIN 55 212-2, naltrexone (an
ultra-low or a high dose) or a combination of WIN 55 212-2 and
naltrexone doses. Tail-flick latencies were recorded for 3 h, at 10-min
intervals for the first hour, and at 15-min intervals thereafter.
Ultra-low dose naltrexone elevated WIN 55 212-2-induced tail flick
thresholds without extending its duration of action. This enhancement
was replicated in animals receiving intraperitoneal or intravenous
injections. A high dose of naltrexone had no effect on WIN 55
212-2-induced tail flick latencies, but a high dose of the cannabinoid 1
receptor antagonist SR 141716 blocked the elevated tail-flick thresholds
produced by WIN 55 212-2+ultra-low dose naltrexone. These data suggest a
mechanism of cannabinoid-opioid interaction whereby activated opioid
receptors that couple to Gs-proteins may attenuate cannabinoid-induced
antinociception and/or motor functioning.
PMID: 16286810 [PubMed - indexed for MEDLINE]
Nat Med. 2007 Feb;13(1):35-37. Epub 2006 Dec 10. Links
Lactobacillus acidophilus modulates intestinal pain and induces opioid
and cannabinoid receptors.
Rousseaux C, Thuru X, Gelot A, Barnich N, Neut C, Dubuquoy
L, Dubuquoy C, Merour E, Geboes K, Chamaillard M, Ouwehand
A, Leyer G, Carcano D, Colombel JF, Ardid D, Desreumaux P.
[1] Institut National de la Sante et de la Recherche Medicale (INSERM)
U795, Hopital Swynghedauw, Rue A Verhaeghe, 59037 Lille Cedex, France.
[2] University of Lille 2, Hopital Swynghedauw, Rue A Verhaeghe, 59037
Lille Cedex, France. [3] Digestive Tract Diseases and Nutrition
Department, Huriez Hospital, 1 Place de Verdun, 59037 Lille Cedex,
France.
Abdominal pain is common in the general population and, in patients with
irritable bowel syndrome, is attributed to visceral hypersensitivity. We
found that oral administration of specific Lactobacillus strains induced
the expression of mu-opioid and cannabinoid receptors in intestinal
epithelial cells, and mediated analgesic functions in the gut-similar to
the effects of morphine. These results suggest that the microbiology of
the intestinal tract influences our visceral perception, and suggest new
approaches for the treament of abdominal pain and irritable bowel
syndrome.
PMID: 17159985 [PubMed - as supplied by publisher]
_________________________
Notes:
peripheral cannabinoid receptor CB2 is highly expressed in immune cell
types (macrophages, dendritic cells, and B cells); Galphai2-/- mice are
deficient in the formation of certain B and T cell subsets and are
susceptible to immune dysregulation, notably developing inflammatory
bowel disease; mice deficient in CB2, the Gi-coupled peripheral
endocannabinoid receptor, have profound deficiencies in splenic marginal
zone, peritoneal B1a cells, splenic memory CD4+ T cells, and intestinal
natural killer cells and natural killer T cells; these findings
partially phenocopy and extend the lymphocyte developmental disorder
associated with the Galphai2-/- genotype, and suggest that the
endocannabinoid system is required for the formation of T and B cell
subsets involved in immune homeostasis [PMID 16924491]
transcription of the CB1 gene in CD4(+) Jurkat T cells was strongly
induced by Delta(9)-tetrahydrocannabinol (THC), whereas the CB2 gene was
not regulated; induction of CB1 gene expression is mediated by CB2
receptors only, as demonstrated by using the CB1 and CB2 agonists
R(+)-methanandamide and JWH 015, respectively, and combinations of THC
plus CB1- and CB2-specific antagonists; after activation of CB2
receptors, the transcription factor STAT5 is phosphorylated; STAT5 then
transactivates IL-4; IL-4 mRNA induction as well as IL-4 protein release
is necessary for the following induction of the CB1 gene;
transactivation of the CB1 gene in response to IL-4 is then mediated by
the transcription factor STAT6; an increase in CB1-mediated
phosphorylation of MAPK in cells prestimulated with CB2-specific
agonists suggests up-regulation of functional CB1 receptor proteins
[PMID 17041005]
cannabinoids may be effective for multiple sclerosis (MS); the
non-selective cannabinoid receptor agonist WIN-2 acts as a suppressive
drug in the experimental autoimmune encephalomyelitis (EAE) model of MS;
in the passive variety of EAE, induced in rats by transfer of
myelin-reactive T cells, WIN-2 ameliorates the clinical signs and
diminishes the cell infiltration of the spinal cord; WIN-2 induced a
profound increase of immune cell apoptosis in a dose- and time-dependent
manner; WIN-2-induced apoptosis of encephalitogenic T cells was
partially blocked by a CB2 antagonist and pertussis toxin but not the
CB1 antagonist, whereas the inactive enantiomer WIN-3 only exerted a
mild effect on cell viability; this points to the partial involvement of
the CB2 receptor together with other receptor-independent mechanism or
by yet unknown cannabinoid receptors; WIN-2 induced the extrinsic
pathway of apoptosis, as shown by caspase-10 and -3 activation [PMID
17007821]
cannabis-based drugs may be of help in IBD; marijuana was smoked in
China and India for this disorder; CB1 receptors line the intestine,
perhaps repairing the gut when damaged; damaged intestinal cells exposed
to synthetic cannabinoids start repairing themselves; CB1 receptors in
the gut also slow gut motility and reduce painful muscle contractions
associated with diarrhea; there is a second type of receptor, CB2, found
in IBD patients which isn't in the healthy guts of normal patients;
these may be associated with suppressing an overactive immune system or
reducing inflammation; chronic inflammation may lead to dysregulation of
the cannabinoid system in the gut
<http://www.newscientist.com/article.ns?id=dn7766>
cannabinoids that bind CB1 are psychoactive, limiting therapeutic use;
JWH-015, a synthetic CB2-selective agonist, triggers apoptosis in
thymocytes in vitro and inhibits the proliferative response of T and B
cells to mitogens through induction of apoptosis; JWH-015 induces
cross-talk between extrinsic and intrinsic pathways of apoptosis
involving caspase-8, caspase-9, and caspase-3 as well as loss of
mitochondrial membrane potential; JWH-015 in vivo caused thymic atrophy,
apoptosis, and decreased peripheral T cell response to mitogens [PMID
17185040] (this means CB2 agonists have effects similar to the general
B-cell deletion agent Rituxan)
repeated use of opiates like morphine results in tolerance to analgesic,
euphoric and repiratory-depressant effects requiring greater doses for
the same response; protein kinase C may play a crucial role in this mu
opioid receptor desensitization [PMID 17000011] |
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| prd |
| Posted: Sat Jan 20, 2007 11:04 am |
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In alt.support.celiac message news:kofi-65E72B.00594320012007
@news.east.earthlink.net by Kofi <kofi@anon.un> . . . :
Quote: cannabis-based drugs may be of help in IBD; marijuana was smoked in
China and India for this disorder; CB1 receptors line the intestine,
perhaps repairing the gut when damaged; damaged intestinal cells exposed
to synthetic cannabinoids start repairing themselves; CB1 receptors in
the gut also slow gut motility and reduce painful muscle contractions
associated with diarrhea; there is a second type of receptor, CB2, found
in IBD patients which isn't in the healthy guts of normal patients;
these may be associated with suppressing an overactive immune system or
reducing inflammation; chronic inflammation may lead to dysregulation of
the cannabinoid system in the gut
http://www.newscientist.com/article.ns?id=dn7766
While smoking cannibis may be an effective means of treat bowel
pain/inflamatory responses it is not recommended mode of entry.
Inhalation is a recipe for getting high, if your goal is to
treat gut inflamation then the drug needs to be released
from time released caplets.
Other than that there are alot of other chemicals in
smoke that do not treat any disease, and some are simply carcinogenic. |
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