Oxytocin antagonist/ inhibitor~ Neuroscience behind premature ejaculation

[nintey]

The title says it all. I am under the impression that oxytocin plays a direct role in premature ejaculation and therefore if there was a way to modulate it, one could possibly gain greater sexual control.

Some of the few things that I have found that have an effect on lowering oxytocin levels are alcohol, opioids and dxm.

Also included in this quote is a short explanation of how ssri's directly affect oxytocin levels and thereby increase sexual stamina

"Interestingly, chronic systemic treatment with
paroxetine and fluoxetine do not change basal oxytocin levels, but attenuate the oxytocin-releasing
response to 5-HT1A receptor agonists [83]. This
attenuation starts after 3 days of treatment and
lasts for at least 60 days after termination of the
treatment [83–87]. Conversely, chronic treatment
with citalopram increased basal plasma oxytocin
levels and did not attenuate the oxytocin-releasing
effect of a challenge dose of the SSRI zimelidine
[88]. As both citalopram and fluvoxamine exert less
ejaculation-delaying effects than paroxetine and
fluoxetine, it is questioned whether the increased
oxytocin levels are associated with the rather mild
ejaculation-delaying effects of citalopram. In this
regard, it is unfortunate that there have been no
reports on the effects of acute or chronic treatment with fluvoxamine on 5-HT-mediated oxytocin release."

Also further backing up my claim is a drug I found that is being developed by glacosmithkline for treatment of P.E~

Epelsiban (GSK-557,296-B) is a drug which acts as an non-peptide oxytocin receptor antagonist, and is being developed by GlaxoSmithKline for the treatment of premature ejaculation in men.(Pyridyl-2,5-diketopiperazines as potent, selective, and orally bioavailable oxytocin antagonists: synthesis, pharmacokinetics, and in vivo potency.)

SO my question is does anyone here have any suggestions on substances or compounds that might have an inhibitory effect on the release of oxytocin beside those that are well know and have undesirable effects

 

[alkap555]

Very recently, we studied the effect of endocannabinoids (ECs) on OXT release. We performed in vitro studies testing the effect of AEA on OXT release from neurohypophysis (NH) (De Laurentiis et al., 2010) and MBH in vitro in normal conditions (Steiner et al., 1997). Several doses of AEA from 10−11 to 10−8 M significantly decreased OXT release from NH, being 10−9 M the most effective inhibitory dose

It appears CB1 agonists (in this case anandamide, or AEA) may inhibit oxytocin release from the posterior pituitary. The putative mechanism involved AEA-mediated modulation of nitric oxide synthase (NOS), as increased NO production has been shown to inhibit magnocellular neuronal (synthesize OXT) activity in the medial hypothalamus.

http://www.ncbi.nlm.nih.gov/pubmed/20353777

So...maybe smoke some weed or a synthetic cannabinoid, preferably one that is selective for CB1.

Hope this makes sense...I am quite sleep deprived at the moment on account of final exams.

 

[Limpet_Chicken]

I'd be curious to try both oxytocin nasal spray/IV oxytocin, and an antagonist like this, given the role of oxytocin in autism.

 

[alkap555]

Correct, oxytocin will not penetrate the BBB if administered intravenously.

There is some (contested) evidence that intranasal administration bypasses the BBB, instead being absorbed by the olfactory epithelium making its way to the CSF via the cribriform plate or the olfactory neurons themselves.

 

[atrollappears]

There is some (contested) evidence that intranasal administration bypasses the BBB, instead being absorbed by the olfactory epithelium making its way to the CSF via the cribriform plate or the olfactory neurons themselves.

This is contested? By whom and with what evidence?

 

[alkap555]

I was mostly basing that off my senior colleagues' opinions and their own research experience with intranasal OXT delivery, but here are two reviews I just stumbled upon:

From nose to brain: understanding transport capacity and transport rate of drugs. In spite of the significant merit of bypassing the BBB, direct nose-to-brain delivery still bears the problems of low efficiency and volume for capacity due to the limited volume of the nasal cavity, the small area ratio of olfactory mucosa to nasal mucosa and the limitations of low dose and short retention time of drug absorption.

http://www.ncbi.nlm.nih.gov/pubmed/18817519

Can nasal drug delivery bypass the blood-brain barrier?: questioning the direct transport theory. No pharmacokinetic evidence could be found to support a claim that nasal administration of drugs in humans will result in an enhanced delivery to their target sites in the brain compared with intravenous administration of the same drug under similar dosage conditions.

http://www.ncbi.nlm.nih.gov/pubmed/17472409

This is well outside my realm of experience...so I apologize if the papers are a few years old--I am aware of newer fMRI studies that do support the intranasal ROA--suppressing amygdala activation in response to aversive/fearful social stimuli and augmenting V.Striatal activity in response to seeing their children "happy" or some nonsense...I'll try and dig it up if/when I have some time.

 

[atrollappears]

Hmm they aren't very old, but this review from back in 2002 presents some pretty good evidence that there is direct non-BBB transport. (This isn't within my realm of experience either.)

"Research in humans has also provided evidence for direct delivery of therapeutic agents to the CNS from the nasal cavity. Studies in humans by Pietrowski and colleagues have demonstrated much greater brain evoked potential changes with intranasal than with intravenous AVP19 or the cholecystokinin analog CCK-8.20 Kern et al.16 have demonstrated CNS effects of intranasal insulin in humans without altering plasma glucose or insulin levels and of intranasal corticotropin-releasing hormone (CRH) without altering plasma cortisol or CRH levels.17 Perras et al.18 have reported that intranasal growth hormone-releasing hormone (GHRH) not only increased rapid eye movement sleep and slow wave sleep in humans, but also decreased growth hormone, which is likely due to a CNS effect of the GHRH following direct delivery to the brain. Finally, Smolnik et al.21 concluded that the action of intranasal ACTH4-10 on human event-related brain potential and attention was due to direct delivery of the peptide from the nose to the brain and did not require prior resorption into the blood. Fehm et al.22 reported that following intranasal administration of MSH/ACTH4-10 to humans, MSH/ACTH4-10 increased significantly in the CSF but not in the blood, and concluded that the peptide directly entered the CNS from the nasal cavity. They also found that intranasal MSH/ACTH4-10 significantly reduced body fat and body weight presumably by acting on the hypothalamic melanocortin system."

http://www.drug-dev.com/ME2/dirmod....91&tier=4&id=65578366323349FB86C1593B14F996D2

 

[alkap555]

Yea on reviewing some papers it seems I am convinced

 

[JBrandon]

Has anyone run across a study that has attempted to delineate the absorption parameters for peptides via this route? I would like to read a little more but I'm not turning up anything.

 

[alkap555]

^^I posted one article about the transport capacity etc of nose-2-brain transpo. Maybe that helps