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        New Message Board Archives >> Medications, Treatments, Therapies 2004 >> fresh research - CH and Orexin
        
(Message started by: floridian on Oct 13th, 2004, 9:09am)
Title: fresh research - CH and Orexin
Post by floridian on Oct 13th, 2004, 9:09am
Hypocretin (aka "orexyn" aka "orexin") is a neurotransmitter with receptors in the hypothalamus.  Having a double dose of the "G" form of the orexin gene seems to be protective against cluster headaches.


Quote:
Neurology. 2004 Oct 12;63(7):1286-8.      

   A polymorphism of the hypocretin receptor 2 gene is associated with cluster headache.

   Rainero I, Gallone S, Valfre W, Ferrero M, Angilella G, Rivoiro C, Rubino E, De Martino P, Savi L, Ferrone M, Pinessi L.

   Neurology III Headache Center, Department of Neuroscience, University of Turin, Via Cherasco 15-10126 Turin, Italy. irainero@molinette.piemonte.it.

   Several polymorphisms of the hypocretin/orexin system genes were evaluated in 109 cluster headache patients and 211 controls. The 1246 G>A polymorphism of the gene was significantly different between cases and controls. Homozygosity for the G allele was associated with an increased disease risk (OR: 6.79, 95% CI, 2.25 to 22.99). The data suggest that the HCRTR2 gene or a linked locus significantly modulates the risk for cluster headache.


Modafinal, a drug for narcolepsy and sleep disorders that was discussed here recently, activates the orexin receptors.  Not sure if Modafinal would be beneficial for CH or not.   Some people with narcolepsy seem to either lack orexin production, or produce antibodies to orexin, which take it out of circulation.  

Orexin is also a hunger stimulant, but it isn't the only one, and it isn't active under all conditions.  A lack of orexin lowers the activity of monoamine neurotransmitters like dopamine, epinephrine, norepinephrine, and serotonin.
Title: Nicotine Upregulates Orexin
Post by floridian on Oct 13th, 2004, 9:19am
Endocrinology. 2000 Oct;141(10):3623-9.      

   Nicotine up-regulates expression of orexin and its receptors in rat brain.

   Kane JK, Parker SL, Matta SG, Fu Y, Sharp BM, Li MD.

   Department of Pharmacology, University of Tennessee College of Medicine, Memphis 38163, USA.

   Orexins are two recently discovered neuropeptides that can stimulate food intake. As the chronic use of tobacco typically leads to a reduction in body weight, it is of interest to determine whether nicotine, the major biologically active tobacco ingredient, has an effect on orexin metabolism in the brain. Using a semiquantitative RT-PCR technique, the levels of messenger RNA (mRNA) for prepro-orexin, orexin A (OX1-R) and orexin B (OX2-R) receptors were 20-50% higher in rats receiving nicotine for 14 days at the level of 2-4 mg/kg day compared with rats receiving saline solvent alone. In animals treated with nicotine at 4 mg/kg x day, the expression levels of mRNA for prepro-orexin, OX1-R, and OX2-R were significantly higher compared with those in either the free-feeding control or pair-fed saline control rats. RIA data indicated that both orexin A and orexin B peptide levels were significantly elevated (45-54%; P < 0.01) in the dorsomedial nucleus (DMH) of the nicotine-treated rats compared with either solvent-only or pair-fed controls. Additionally, orexin B was significantly elevated (83%; P < 0.01), over levels in both types of the control animals, in the paraventricular nucleus (PVN) region. In summary, we demonstrated that an inverse association between nicotine and food intake as well as body weight held with doses comparable to those consumed by average human smokers. Moreover, our data indicated that chronic exposure to nicotine can induce a long-term increase in the expression levels of prepro-orexin and their receptor mRNA in the rat hypothalamus and in the levels of orexin A in the DMH and orexin B in the DMH and PVN among the six hypothalamic regions that we examined.
Title: Orexin reduces Melatonin
Post by floridian on Oct 13th, 2004, 9:27am
Orexin can reduce melatonin production.


Quote:
Eur J Neurosci. 2001 Aug;14(3):419-25.      

   Hypocretin (orexin) in the rat pineal gland: a central transmitter with effects on noradrenaline-induced release of melatonin.

   Mikkelsen JD, Hauser F, deLecea L, Sutcliffe JG, Kilduff TS, Calgari C, Pevet P, Simonneaux V.

   Department of Neurobiology, H. Lundbeck A/S, Copenhagen, Denmark.

   Hypocretin-1 (HCRT-1) and hypocretin 2 (HCRT-2), also known as orexin-A and orexin-B, are two neuropeptides derived from the same precursor. Hypocretinergic neurons have been found exclusively in the hypothalamic dorsolateral area. These neurons are implicated in sleep and feeding through activation of specific G-protein-coupled orexin-1 and orexin-2 receptor (OR-R1 and OR-R2). The purpose of this study was to determine the existence of the HCRT peptides in the central input of the rat pineal gland. Further, OR-R1 and OR-R2 expression was determined in the pineal gland and the effect of HCRT-2 on melatonin synthesis and secretion was analysed in dissociated rat pinealocytes. A large contingent of HCRT-positive nerve fibres and terminals were observed in the epithalamus, many of which entered into the pineal parenchyma. A significant number of nerve fibres endowed with positive boutons were identified in the pineal stalk, though the number of positive fibres decreased along the extension of the stalk. So far, no positive fibres have been found in the superficial pineal gland. RT-PCR analysis revealed the expression of OR-R2 mRNA, whereas OR-R1-receptor mRNA was not detected. When tested alone, HCRT-2 had no effect on secretion of melatonin from cultured rat pinealocytes. However, HCRT-2 partially inhibited (by a maximum of 30%) the beta-adrenergic-induced melatonin secretion. The same effect was seen on activation of N-acetyltransferase activity. The distribution and the large number of HCRT-positive fibres together with the effect on noradrenaline-mediated melatonin release through specific receptors suggests that these peptides may be significant central transmitters in pineal function, probably mediating homeostatic signals to the pineal gland.
Title: Re: fresh research - CH and Orexin
Post by ozzy on Oct 13th, 2004, 10:31am
Hard to decipher, but If you somehow increase the orexin type G, it may be a potentially effective treatment for CH. I guess CHrs have too much A type, therefore have melatonin problems. One way to supress A type is to smoke. By supressing A type, you have relatively more G type and therefore, smoking is effective for CHrs?

Then again, I probably didn't understand a thing....


Ozzy
Title: Re: fresh research - CH and Orexin
Post by JJA on Oct 13th, 2004, 12:48pm
I'd say it's way too soon to start thinking smoking would help CH in the long run.

Nicotine is an appetite suppressant.  Orexin is an appetite stimulant.  You would expect nicotine to decrease orexin, but it doesn't. Nicotine increases orexin expression (mRNA measured by RT-PCR) and orexin production or release. (orexin measured by RIA)

Maybe this is because nicotine blocks orexin receptors and orexin production is therefore increased by a "biofeedback mechanism."  At least this way the data make sense.  

On the other hand, since nicotine seems to increase orexin expression, this could cause decreased melatonin levels possibly making smoking bad for CH.  I guess my point is that it's complicated.

Anyone have the full text?

Thanks for the info Floridian.

Jesse

Edited to say I got the full text.
Title: Re: fresh research - CH and Orexin
Post by nani on Oct 13th, 2004, 1:10pm
Good Lord you guys are smart!  When you figure it all ou can you post in regular people words so I can get it?  [smiley=laugh.gif]
Title: Re: fresh research - CH and Orexin
Post by floridian on Oct 13th, 2004, 1:28pm
I haven't fully digested this orexin stuff, and am not suggesting that nicotine would help prevent clusters.  It could be just the opposite, not sure on that. Just putting out a few threads.

Complicated?  Yeah, its like the economy.  Doubling the price of oil sends the economy into a steep recession, except when it doesn't.  How a complex animal like the brain or the economy responds to a single factor can't always be predicted without considering a few thousand other things.  
Title: Re: fresh research - CH and Orexin
Post by JJA on Oct 13th, 2004, 2:49pm

on 10/13/04 at 13:28:18, floridian wrote:
I...am not suggesting that nicotine would help prevent clusters.


I didn't think you were.  In fact I am very grateful to your generous sharing of information in a very objective way.  I was just being devil's advocate to Ozzy's post (sorry Ozzy, no disrespect intended).  

Jesse
Title: Re: fresh research - CH and Orexin
Post by ozzy on Oct 13th, 2004, 3:14pm
No offense taken Jesse, just trying to figure it out myself.

One thing that is confusing, is that, the first article talks of two different Orexin (A and G), the following ones talk about (A and B) and/or (1 and 2).

G type seem to play a key for us, as does A.

An imbalance anywhere seems to cause havoc in our brains (as is true for the rest of the population), we have managed so far to treat the symptoms and are still looking for the root of it all, hypothalamus might only be part of the answer, not sure about that either.

So what is wrong with supressing the symptoms? We run the risk of screwing something else up. In the end there may not be a "perfect balance" but only a quality of life issue.

Ozzy
Title: Re: fresh research - CH and Orexin
Post by Woobie on Oct 13th, 2004, 3:39pm

on 10/13/04 at 13:10:43, nani wrote:
Good Lord you guys are smart!  When you figure it all ou can you post in regular people words so I can get it?  [smiley=laugh.gif]





Ditto!   [smiley=laugh.gif]

I'm not the brightest crayon in the box ..........
Title: Re: fresh research - CH and Orexin
Post by JJA on Oct 13th, 2004, 4:09pm
Ozzy,

My thought on the different Orexins is this.  There is Orexin A and Orexin B [aka Hypocretin-1 (HCRT-1) and Hypocretin 2 (HCRT-2)].  Orexin G or "1246 G>A polymorphism" refers to the genes which code for Orexin receptors.  The #'s refer to Orexin receptors (Orexin A (OX1-R) and Orexin B (OX2-R) receptors)  

More simply:
G is a gene
A and B are neuropeptides and
1 and 2 are receptors

Just my interpretation though, I never heard of an orexin before today.

Jesse

Edit: The gene codes for orexin receptor2, not orexin A or B.
Title: Re: fresh research - CH and Orexin
Post by Rock_Lobster on Oct 21st, 2004, 10:06am
I am going to put Orexin on my wifes grocery list.  'G' flavor, right?
Title: Re: fresh research - CH and Orexin
Post by ozzy on Oct 21st, 2004, 10:07am
Thanks floridian for your timely posts. For a full article, see the thread BINGO! CH DISCOVERY! by Luciano:


http://www.clusterheadaches.com/cgi-bin/yabb/YaBB.cgi?board=general;action=display;num=1098345136




Ozzy
Title: Re: fresh research - CH and Orexin
Post by Valerie on Oct 21st, 2004, 10:43am
I sure am glad we have you guys on our side!  None of this makes sense to me - I appreciate the research you all are doing  :)  :)  :)

Valerie


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