[MUSIC] Welcome back, we're going to continue talking about milk ejection and we've talked in other videos about the process of milk ejection, about oxytocin. want to spend a little bit of time thinking about inhibition though, how the process is inhibited. Before we do that though, I want to start out to remind you of the milk ejection reflex, the process. Again, manipulation of the mammary gland. The calf suckling on the teats or whatever the case may be, sends nerve impulses to the brain. That's the white line up, going up here, very very fast. Results in release of oxytocin from the posterior pituitary that travels back the other blood, the red line here, to the mammary gland, causing contractions of mioepithelial cells. Around those ovule lines small ducts, squeezing the milk out illuminally ovule lines small ducts down through the tissue. That's the normal process, but certainly, this is sometimes inhibited, or there's inhibitions going on with regard to that pathway. Now if we look at this, we might start to recognize pretty quickly, well there's at least two spots at which this could be inhibited. One would be at the brain, we call that central inhibition. And the other would be at the level of the udder, the response of the mammary gland to the oxytocin, or to the stimulation of milk ejection. That would be called peripheral inhibition. So let's start with the central inhibition, go to the first slide. Again, it occurs at the level of the brain. What do we know about this? We know, for example, that opioid agonists inhibit milk ejection in general. An example of that would be morphine. Morphine inhibits oxytocin release during milking in cows. So again, what's happening is that opioids of one sort or another in the brain, in the central part of the nervous system and speaking specifically the brain, are somehow inhibiting release of oxytocin. And that, then, inhibits milk ejection at the mammary gland level. The flip side of that is we know that opioid antagonists, naloxone being one of those, can actually enhance oxytocin release. In this particular case, they were looking at using the vagino-cervical stimulation. Again, remember, distending the vagina, distending the cervix, manipulating those can cause an oxytocin release from the posterior pituitary. That's actually enhanced with opioid antagonists. So central inhibitions usually occurring by some mechanism that involves these kinds of opioid antagonists one way or the other. Go to the next slide. Peripheral inhibition on the other hand, again, something's happening here at the mammary gland level. Catecholamines, epinephrine, norepinephrine. You may also know those by the names of adrenaline. Adrenaline is epinephrine, they're the same thing. Noradrenaline or norepinephrine, again, the same thing coming from the adrenal gland. Inhibit milk ejection, even when there's high levels of oxytocin, which starts to raise some issues about what's the mechanism by which these things are acting. And we'll get to that here in just a moment. [COUGH] These effects do not seem to be caused by interfering with oxytocin receptors. So they're not being released from the adrenal gland going to the mammary gland and somehow interacting with the oxytocin receptors and preventing those from binding to oxytocin. Because again, even very high levels of oxytocin cannot overcome that inhibition, so there's some other mechanism going on there. And again, we'll touch on that here in a second. Before I get to that, though, just very generally, peripheral inhibition is usually only observed under experimental conditions. So that's not normally happening in case of inhibition of milk ejection. But certainly, you can make it happen experimentally. Frankly, it's really usually the central kind of inhibition that's happening in most cases. Let's go to the next slide. So let's examine this just a little bit further in terms of peripheral inhibition because we start to kind of get into another concept here. Inhibition caused by adrenergic agonist, adrenaline, epinephrine and so on. May occur by increasing sympathetic tone in the milk ducts and the cistern. So what do we mean by sympathetic tone, let's go to the next slide. This is a classic picture I've shown you before in mammary structure and other videos of the teat cistern here, the gland cistern, the matrix external ducts here up in the gland, very large. And this image kind of projects the idea that these are just wide open all the time and that's not necessarily the case. They are actually relatively constricted between milkings. So this would actually be much smaller than this, this would be much smaller than this. When milk ejection occurs, these tend to relax as milk's being forced down there, increasing intermammary pressure. They actually expand, so we see the sympathetic tone. The sympathetic tone, again, is keeping these things contracted a bit. Decreases during milking, during milk ejection. And increases between milkings. What we think is going on is that these catecholamines are really acting at that level rather than up at the alveolar level or the myoepithelial level and somehow interfering with the effects of oxytocin. So they're really slowing down or preventing milk ejection because these don't relax and allow milk to come out. Milk flow to really be very effective at that point. To the next slide. So just to very briefly review what we've talked about here. We have two levels of inhibition, central inhibition and peripheral inhibition. This is probably relating more to again this idea of sympathetic tone here. Central inhibition, yes it's happening, it's happening in response to opiode type agonist. Morphine again, was one of the examples that we gave. And very likely this is where things are happening because certainly inhibition of milk ejection does occur. It occurs in particularly first calf heifers. They will not let their milk down. It occurs in lactating women sometimes and occurs in a variety of species. Often because of some sort of stress or another. That stress is not related to corsal. Corsals actually increase during milking. So this inhibition can't be because of corsal or good cocorticoids. It's probably more something going on up here at the brain level. Inhibiting the oxytocin release, or at least inhibiting it enough so you don't get a response down here at the memory gland level.
