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View Full Version : Naltrexone to block feedback inhibition?



Dr Pangloss
03-21-2009, 01:35 PM
The following animation is a brief and simplified synopsis of the role of beta endorphin and enkephalin (ie, endogenous opioids) in mediating the estrogen, progesterone, and testosterone-mediated feedback onto hypothalamic neurons.

In summary, the common modulators of feedback-mediated LH and Testosterone shut-down appear to be endogenous opioids.

This makes the opioid signalling an ideal target for inhibiting the suppression or shut-down that normally occurs with steroid use.

I will post papers relating to this following the animation.


By the way, this was at the suggestion of Maxititer. After reviewing the literature, i think this could be represent an excellent addition to pct, and an excellent way to limit shut-down while on-cycle.

Dr Pangloss
03-21-2009, 01:38 PM
6991

Dr Pangloss
03-21-2009, 01:45 PM
my apologies. The quality of the pic sucks.


The words on the upper-right are: Estrogen and/or progesterone enhance
beta-endorphin and enkephalin release from neurons that impinge on GnRH-releasing neurons. The enhnanced opioid release shuts down GnRH secretion.



•Opioid antagonists have been shown to increase
both LH and testosterone, probably by blocking
Estrogen/progesterone-mediated increased opioid
release. Opioid antagonists block the inhibitory
effects of testosterone as well.



• This represents a potentially effective means of
blocking feedback inhibition to the hypothalamus
from all sources. At least feedback to the hypothalamus...



•Naltrexone, a long-acting opioid antagonist, is
probably the best option for this.

Dr Pangloss
03-21-2009, 01:50 PM
: Physiol Behav. (javascript:AL_get(this, 'jour', 'Physiol Behav.');) 2009 Feb 16;96(2):333-42. Epub 2008 Nov 7.http://www.ncbi.nlm.nih.gov/corehtml/query/egifs/http:--linkinghub.elsevier.com-ihub-images-PubMedLink.gif (http://www.ncbi.nlm.nih.gov/entrez/utils/fref.fcgi?PrId=3048&itool=AbstractPlus-def&uid=19027764&db=pubmed&url=http://linkinghub.elsevier.com/retrieve/pii/S0031-9384(08)00339-9) Links (javascript:PopUpMenu2_Set(Menu19027764);)

Naltrexone effects on male sexual behavior, corticosterone, and testosterone in stressed male rats.

Retana-Márquez S (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Retana-M%C3%A1rquez%20S%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Bonilla-Jaime H (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Bonilla-Jaime%20H%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Vázquez-Palacios G (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22V%C3%A1zquez-Palacios%20G%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Martínez-García R (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Mart%C3%ADnez-Garc%C3%ADa%20R%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus).
Department of Biology of Reproduction, Universidad Autonoma Metropolitana-Iztapalapa, San Rafael Atlixco 186, Mexico City C.P. 09340, Mexico. rems@xanum.uam.mx
Chronic physical or psychological stress disrupts male reproductive function. Studies in our laboratory have shown that stress by immersion in cold water (ICW) and by electrical foot shocks (EFS) has inhibitory effects on male sexual behavior; these effects do not seem to be mediated by an increase in corticosterone, nor by a decrease in testosterone. On the other hand, it is known that endogenous opioids are released in the brain in response to these same stressors; consequently, they could be participating in the impairment of sexual behavior, as well as in the changes in corticosterone and testosterone caused by stress. The aim of this study was to analyze the effects of the opioid antagonist naltrexone (NTX) on male sexual behavior, corticosterone, and testosterone in both stressed sexually experienced and naive male rats. Sexually experienced adult male rats were assigned to one of the following groups (n=10 each): 1) control group, males without sexual evaluation; 2) control group, rats injected ip with saline, non-stressed; 3) control group, rats injected with NTX (3 mg/kg) non-stressed; 4) rats injected ip with saline, and stressed by EFS; 5) rats injected ip with NTX (1.5 mg/kg) and stressed by EFS; 6) rats injected ip with saline and stressed by ICW; 7) rats injected ip with NTX (1.5 mg/kg) and stressed by ICW; 8) rats injected ip with NTX (3 mg/kg) and stressed by ICW. Naive males were assigned to the same control groups but only stressed by ICW and the NTX dose used was 3 mg/kg. Injections were given 30 min before stress sessions. Stress was applied on 20 consecutive days. Male sexual behavior was assessed 15 min after EFS or 30 min after ICW, on days 1, 4, 8, 12, 15, and 20. Trunk blood was collected at the end of the experiments on day 20 of stress. Corticosterone and testosterone were evaluated by HPLC. Mount, intromission and ejaculation latencies were longer in control saline naive males compared to control saline sexually experienced males on the first day. NTX administration to control naive males caused a decrease in mount, intromission, and ejaculation latencies, as well as an increase in ejaculatory frequency/30 min, compared to control-saline only on day 1. Stressed naive males showed higher mount, intromission and ejaculation latencies, compared to control and stressed sexually experienced males, as well as comparable increase in corticosterone and decrease in testosterone plasma levels. NTX administration before exposure to stress prevented the modifications caused by stress in sexual parameters. Sexual behavior in control sexually-active males injected with saline or NTX was not modified. Saline stressed males showed the previously reported alterations in sexual behavior, as well as an increase in corticosterone and a decrease in testosterone plasma levels. Stressed males injected with NTX before exposure to stress showed no alterations in male sexual behavior. NTX in control non-stressed males did not modify corticosterone plasma levels, but did cause a significant increase in plasma testosterone. The increase in corticosterone and the decrease in testosterone due to stress, were attenuated with the opioid antagonist, both in naive and sexually experienced males. Prevention of ICW stress effects was more effective with higher doses of NTX (3 mg/kg). These data suggest that endogenous opioids could be participating in the effects caused by stress on male sexual behavior, corticosterone, and testosterone.

Dr Pangloss
03-21-2009, 01:52 PM
as above, be patient. There are many papers related to this.

Also, there must be a reasonable discussion of dose.

Dr Pangloss
03-21-2009, 01:56 PM
1: Pharmacol Biochem Behav. (http://javascript<b></b>:AL_get(this, 'jour', 'Pharmacol Biochem Behav.');) 2000 Jun;66(2):275-83.http://www.ncbi.nlm.nih.gov/corehtml/query/egifs/http:--linkinghub.elsevier.com-ihub-images-PubMedLink.gif (http://www.ncbi.nlm.nih.gov/entrez/utils/fref.fcgi?PrId=3048&itool=AbstractPlus-def&uid=10880679&db=pubmed&url=http://linkinghub.elsevier.com/retrieve/pii/S0091-3057(00)00190-8) Links (http://javascript<b></b>:PopUpMenu2_Set(Menu10880679);)

Acute effects of nalmefene on LH, prolactin, and testosterone in male rhesus monkeys.

Mello NK (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Mello%20NK%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Mendelson JH (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Mendelson%20JH%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Kelly M (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Kelly%20M%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus).
Endocrine Unit, Alcohol and Drug Abuse Research Center, McLean Hospital-Harvard Medical School, 115 Mill Street, Belmont, MA, 02478, USA.
The effects of the long-acting opioid antagonist, nalmefene [17-N-cyclopropylmethyl-3,14-beta-dihydroxy-4, 5-alpha-epoxy-6-methylene morphinan hydrochloride] on LH, T, and prolactin release in rhesus monkeys are unknown. The acute effects of nalmefene (0.01 and 0.10 mg/kg, IV) or placebo on LH, PRL, and T were studied, and samples were collected at 10-min intervals for 360 min to permit cluster analysis of pulsatile release patterns. LH increased significantly within 30 min after nalmefene, and remained significantly above baseline levels for 50 to 60 min (p < 0.05). Testosterone increased significantly within 70 to 80 min after nalmefene, and remained significantly above baseline for 60 min (p < 0.05). Although nalmefene antagonizes opioid agonists for 6-8 h, inhibitory feedback by testosterone appeared to limit the duration of its antagonism of endogenous opioid inhibition of LHRH and stimulation of LH. Nalmefene did not change LH or PRL pulse frequency or amplitude significantly in comparison to placebo administration.

Dr Pangloss
03-21-2009, 02:00 PM
1: Arch Androl. (javascript:AL_get(this, 'jour', 'Arch Androl.');) 1996 Jul-Aug;37(1):15-8. Links (javascript:PopUpMenu2_Set(Menu8827343);)

Effect of naloxone on serum testosterone in adult male rabbits.

Pedrón N (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Pedr%C3%B3n%20N%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Pedroza D (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Pedroza%20D%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Calzada L (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Calzada%20L%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Salazar L (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Salazar%20L%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Fuentes V (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Fuentes%20V%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus).
Unidad de Investigación Médica en Biología de la Reproducción, IMSS, México DF, México.
Considerable evidence suggests that endogenous opioids may play an important role in the hypothalamic LH-releasing hormone. Administration of high doses of naloxone, an opiate antagonist, produces an increase in plasma concentration of LH. Naltrexone administration to healthy males produces an increase in both immunoactive and bioactive LH. The objective of the present work was to assess the effect of low doses of naloxone during 10 consecutive days on testosterone serum levels in rabbit. Three groups of five rabbits were injected with naloxone or saline. Naloxone was tested at 0.1 and 0.01 mg/kg day-1. Blood samples were taken at 90 min and 1, 2, 4, 7, 10, and 14 days after starting naloxone administration. Plasma testosterone (T) levels were measured by RIA. T levels increased progressively through the study in the experimental groups. The differences were significant after days 4 and 7 for 0.01-mg/kg and 0.1-mg/kg doses, respectively. T levels in both groups peaked at day 10 and decreased at day 14 (4 days after treatment).

Dr Pangloss
03-21-2009, 02:02 PM
more later...

SonOfPluto
03-23-2009, 02:08 AM
Interesting, does this mean then that chronic intake of exogenous opioids such as morphine and codeine inhibits testosterone production?

Dr Pangloss
03-23-2009, 07:10 AM
to some extent, yes. Also with alcohol.

angelo212
03-29-2009, 11:18 PM
So what dose do you think would do some good? I already take 2mg a day which is a very low dose. There is a very popular yahoo group dedicated to LDN (low dose naltrexone) There are alot of studies saying it may be good for many different ailments. Not sure I buy into that to much. They list everything from cancer to aids MS, etc. There is some research though. I take it for medical purposes.

Dr Pangloss
03-30-2009, 06:12 PM
So what dose do you think would do some good? I already take 2mg a day which is a very low dose. There is a very popular yahoo group dedicated to LDN (low dose naltrexone) There are alot of studies saying it may be good for many different ailments. Not sure I buy into that to much. They list everything from cancer to aids MS, etc. There is some research though. I take it for medical purposes.



i left the dose out because all the demonstrations of effects on Test or LH levels have been done with substantial amounds of naltrexone.

That said, the inhibition of craving occurs at very low dose like 0.25 mg ed. This is operating on the same signal transduction pathways that would lead to the increase in Test, so there is an effect. It's probably just substantially smaller at 2 mg ed.

Dr Pangloss
04-12-2009, 09:12 AM
I just started this at 2 mg ed and i noticed an immediate effect on libido. The first day i took it i noticed it. IMO, naltrexone has to be working to increase Test even at 2 mg.

Dr Pangloss
04-13-2009, 06:08 PM
initial use of naltrexone even at low dose is associated with vivid and persistent dreams at night. I, for one, can verify that...

Dr Pangloss
04-15-2009, 08:06 PM
for those of you that aren't aware, naltrexone at low dose has also been shown to inhibit alcholol cravings.....


I'm hoping Foremanrules will see this...:D

Dr Pangloss
05-04-2009, 07:26 PM
found out today naltrexone is likely raising my blood pressure. I measured my diastolic at 94 today. Eeek.

I'm going to once per week at 2mg.

maxititer
05-05-2009, 01:12 PM
nice thread mate !
time to wake up.
naltrexon is very valuable drug to be missed.

maxititer
05-05-2009, 01:19 PM
found out today naltrexone is likely raising my blood pressure. I measured my diastolic at 94 today. Eeek.

I'm going to once per week at 2mg.

not necessary from naltrexon. I'm using it regularly for more then a year.

I'm 50 and only BP which I'm getting (from time to time) is associated with high hematocrit. Then I letting 20ml of blood out and it will last for a while, depends of which kind of AAS I'm using.

what is your arterial tension value, systolic minus diastolic.

Dr Pangloss
05-05-2009, 01:38 PM
not necessary from naltrexon. I'm using it regularly for more then a year.

I'm 50 and only BP which I'm getting (from time to time) is associated with high hematocrit. Then I letting 20ml of blood out and it will last for a while, depends of which kind of AAS I'm using.

what is your arterial tension value, systolic minus diastolic.

well, first of all this is listed as a side effect of a small number of patients (1%).

My values went from 130-135 over 78-83 to 130s-140s over 90-94. So it seems to be raising the diastolic.

Dr Pangloss
05-05-2009, 02:45 PM
remember also, maxititer, that i had been taking 2 mg ed. I simply cut the dose to once or twice a week.

maxititer
05-05-2009, 04:22 PM
sure possible, initially I also took 50 mg at once, as it is advised in books and in naltrexone box printout, then was vomiting for few days and got some headache. Took me a while to get interested in naltrexone again.

keep posted how it will go

Dr Pangloss
05-05-2009, 04:49 PM
sure possible, initially I also took 50 mg at once, as it is advised in books and in naltrexone box printout, then was vomiting for few days and got some headache. Took me a while to get interested in naltrexone again.

keep posted how it will go


will do. I very much liked it until this cropped up. Everything is dose-dependent, so i imagine its a matter of finding a happy equilibrium.

Klaus Urine
06-14-2009, 04:33 PM
will do. I very much liked it until this cropped up. Everything is dose-dependent, so i imagine its a matter of finding a happy equilibrium.So, a happy medium was found at 1mg EOD?

I'm wondering where you guys get this dosing idea if all the studies used comparatively huge doses.

Dr Pangloss
06-14-2009, 04:43 PM
So, a happy medium was found at 1mg EOD?

I'm wondering where you guys get this dosing idea if all the studies used comparatively huge doses.


there are studies all over the map on naltrexone, from early studies that use 50-100 mg ed (total overkill) to low dose (1-5 mg ed) to very low dose (0.2-0.9 mg ed).

there is doubtless a smaller effect at lower dose, and that's why i suggested not using it singly for pct.

But low dose studies have shown effects on LH and Test levels also, and effects on the immune system and alcohol craving.

i'm actually not sure if low dose increases cort levels--the cort levels study was very old-- but i imagine it does somewhat.