Mice born without a functional CB1 receptor experience HPA axis
dysregulation, including higher secretion of ACTH. This mutation
enhances the circadian HPA axis activity peak and leads to central
impairment of glucocorticoid feedback [PMID 17194743].
This result may be applicable in common human conditions. The loss of
gut bacteria colonies in humans can cause a drop in CB1 receptor levels
<http://www.newscientist.com/article/dn10808.html>,
[PMID 17159985],
resulting in chronic pain and inflammation. Individuals with a drop in
friendly gut bacteria often experience autoimmunity and HPA axis
dysregulation (e.g., allergies and insomnia). I think the CB1 receptor
may help explain this association.
If true then loss of CB1 function might be a factor in everything from
adrenal failure and inflammation to hyperactivity/attention deficit
disorder (ADHD). Given what's going on and where, I should think any
prolonged elevation of ACTH might also serve to incline the body toward
developing autoantibodies to ACTH thus eventually lowering cortisol
response - resulting, for instance, in chronic infection or the
condition commonly refered to as "adrenal failure" - borderline low DHEA
and/or cortisol. You can see ACTH autoantibodies in Addison's Disease,
chronic aggressiveness, anorexia nervosa and bulimia. Thus through a
roundabout manner, loss of CB1 signaling might ultimately stimulate a
drop in cortisol similar to that seen in chronic stress. It might also
fiddle with circadian rhythms and I wonder if it might be responsible
for some of the insomnia associated with allergies.
Once these conditions get underway - perhaps from something as simple as
antibiotic overuse - I doubt they are quite as easily reversed.
Low-dose naltrexone is certainly helpful restoring mu opioid receptor
function. It's probably dragging along the cannabinoid receptors to
some extent. What would really be interesting to throw at these
digestive problems is a low-dose dual cannabinoid antagonist, but to my
knowledge nobody's ever tried that. I think this new research
establishes a rationale for trying low-dose cannabinoids in such adrenal
dysfunction cases.
If you're interested in this, I've written extensively before about how
changes in mu opioid/CB1/CB2 apply to Crohn's, IBD and other autoimmune
digestive disorders.
Endocrinology. 2007 Apr;148(4):1574-81. Epub 2006 Dec 28.
Requirement of cannabinoid receptor type 1 for the basal modulation of
hypothalamic-pituitary-adrenal axis function.
Cota D, Steiner MA, Marsicano G, Cervino C, Herman JP, Grubler Y, Stalla
J, Pasquali R, Lutz B, Stalla GK, Pagotto U.
Group of Clinical Neuroendocrinology, Max Planck Institute of
Psychiatry, Munich, Germany.
The endocannabinoid system affects the neuroendocrine regulation of
hormone secretion, including the activity of the
hypothalamus-pituitary-adrenal (HPA) axis. However, the mechanisms by
which endocannabinoids regulate HPA axis function have remained unclear.
Here we demonstrate that mice lacking cannabinoid receptor type 1
(CB1-/-) display a significant dysregulation of the HPA axis. Although
circadian HPA axis responsiveness is preserved, CB1-/- mice are
characterized by an enhanced circadian drive on the HPA axis, resulting
in elevated plasma corticosterone concentrations at the onset of the
dark as compared with wild-type (CB1+/+) littermates. Moreover,
CB1-/--derived pituitary cells respond with a significantly higher ACTH
secretion to CRH and forskolin challenges as compared with pituitary
cells derived from CB1+/+ mice. Both CBL-/- and CB1+/+ mice properly
respond to a high-dose dexamethasone test, but response to low-dose
dexamethasone is influenced by genotype. In addition, CB1-/- mice show
increased CRH mRNA levels in the paraventricular nucleus of the
hypothalamus but not in other extrahypothalamic areas, such as the
amygdala and piriform cortex, in which CB1 and CRH mRNA have been
colocalized. Finally, CB1-/- mice have selective glucocorticoid receptor
mRNA down-regulation in the CA1 region of the hippocampus but not in the
dentate gyrus or paraventricular nucleus. Conversely, mineralocorticoid
receptor mRNA expression levels were found unchanged in these brain
areas. In conclusion, our findings indicate that CB1 deficiency enhances
the circadian HPA axis activity peak and leads to central impairment of
glucocorticoid feedback, thus further outlining the essential role of
the endocannabinoid system in the modulation of neuroendocrine functions.
Publication Types:
* Research Sup****t, Non-U.S. Gov't
PMID: 17194743
_________________
Notes
_________________
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 isnıt 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>
friendly gut bacteria - lactobacillus acidophilus - found in yoghurt and
probiotics boosts the synthesis of receptors for mu opioids and
cannabinoids (CB1 and CB2) - our natural painkillers - in human and
rodent gut cells; rats given probiotics experienced a 20% increase in
their pain threshold or twice that if they had irritable bowel syndrome;
the analgesic effect was similar to morphine and suggests the
microbiology of the intestinal tract influences our visceral perception
<http://www.newscientist.com/article/dn10808.html>,
[PMID 17159985]
low-dose naltrexone works for 76% of a group of 42 patients with
irritable bowel syndrome; it improved pain and other symptoms; the mean
weekly number of pain-free days increased from 0.5+/-1 to 1.25+/-2.14
[PMID 17080248]; low dose naltrexone enhances cannabinoid-induced
antinociception (i.e., raised the pain threshold in rats); a high dose
has no effect; a cannabanoid antagonist stopped the combination from
working; this suggests a mechanism of cannabinoid-opioid interaction
where activated opioid receptors couple to Gs-proteins and attenuate
cannabinoid-induced antinociception and/or motor functioning; LDN also
enhances the effects of morphine and other mu opioid agonists [PMID
16286810]
Rimonabant, a cannabinoid receptor 1 (CB1) blocker, inhibits
upregulation of the androgen receptor in prostate cancer cells [PMID
14675774] as well as short-circuiting the reward circuitry in the brain
and helping people to quit smoking and lose weight; CB1 receptor
activation blocks glutamate release [PMID 14657164] and is generally
protective of excitotoxicity [PMID 14526074]; cannabinoid agonists
decrease sensitivity to the passage of time, perhaps contributing to
attention deficit [PMID 12946595]; CB1 receptor blocker rimonabant
blocks TNF-a in the gut [PMID 12967941]; 20mg rimonabant helps patients
lose more than 12 pounds and improves lipid readings (LDL, HDL,
triglycerides) beyond what one would expect from the weight loss alone
<http://www.newscientist.com/channel/health/dn8724.html>
autoimmune Addisonıs disease (AAD) is a chronic disease with a long
preclinical period of high adrenal cortex autoantibodies; those at
particular risk of developing AAD are first degree relatives of patients
with AAD and patients with existing autoimmune diseases, especially
those with chronic hypoparathyroidism or premature ovarian failure;
adrenal cortex function in these people is *****sed via basal
determination of ACTH, cortisol, aldosterone, plasma renin activity and
cortisol after ACTH stimulation; future AAD risk depends on antibody
titers, chronic hypoparathyroidism or chronic candidiasis and adrenal
dysfunction [PMID 15826924]
chronic ACTH autoantibodies impair the bodyıs cortisol response and are
a significant pathological factor in the disruption of the HPA axis in
chronic fatigue syndrome, anorexia nervosa and major depression; anxiety
and self-injury can be psychological symptoms of compensating for less
effective ACTH; self-injury can increase cortisol levels; corticosteroid
therapy is an effective treatment for all three conditions because it
allows the patients to have the corticosteroids they need for daily
functioning and daily stressors [PMID 15885924]
patients with celiac can develop autoantibodies against endocrine glands
[PMID 10925978]
aggressive behavior is linked to autoantibodies for corticotropin
(ACTH); altered stress response is characteristic of individuals with
abnormal aggressive and antisocial behavior; in tests of Swedish males
with conduct disorder and prisoners with a violent record, both groups
displayed strongly increased levels of ACTH-reactive immunoglobuilin G
and M (IgG and IgM) autoantibodies compared with control subjects; IgM
oxytocin antibodies were slightly elevated in both groups whereas
vasopressin-reactive antibodies were lower only in conduct disorder; no
antibody differences for alpha-MSH were observed [PMID 16876133]
a majority of patients with anorexia nervosa and bulimia nervosa as well
as some controls have autoantibodies reacting with alpha-MSH or ACTH,
melanocortin peptides involved in appetite control and stress-response;
antibodies to oxytocin (high in women after ***) and vasopressin
(necessary for pair-bonding) were also present in all three groups;
specifically there were increased IgM antibodies against alpha-MSH,
oxytocin and vasopressin as well as IgG antibodies against vasopressin
in anorexia patients compared with bulimics and controls; there were
significantly altered correlations between anti-alpha-MSH titers and
total Eating Disorder Inventory-2 scores as well as most of its subscale
dimensions in anorexia and bulimia patients vs. controls; these
correlations were opposite in anorexics compared to bulimics; antibodies
to oxytocin, vasopressin and ACTH had only few altered correlations
[PMID 16195379]
hypercortisolism and diabetes tend to cluster together; cortisol
encourages appetite for high calorie foods; prolonged psychological
stress suppressed morning cortisol and tem****arily reduces cortisol
response to ACTH [PMID 14974927]
CB1 receptor deficient mice have trouble forgetting fear conditioning
and extingui****ng averse memories; endogenous cannabinoids im****tant in
long-term depression of GABA-mediated inhibition [PMID 12152079] (this
proclivity to post-traumatic stress may have to do with the elevated
ACTH response)
caffeine activates parts of the pituitary-adrenocortical response during
the resting state; increases ACTH and increases cortisol production
when exercising at high intensity under warmer conditions, opioid
receptor blocker naloxone hastens exhaustion; plasma ACTH, growth
hormone and beta-endorphin increased under the heat with naloxone and
decreased with cold exposure [PMID 16468062]
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