Parsing Papers 4 – The Neurobiology of Pain Sensitivity (Part IV)

(follow-up to Parsing Papers 3 – The Neurobiology of Pain Sensitivity (Part III))

Google “action potential” and you see a graph that looks a bit like a mountain with flat land on the left side and a valley on the right.

It’s a common enough icon of neuroscience (second only to gratuitous blue brains), but what does it mean?

Since we figured out this resting membrane potential business last time, now we can consider what happens when that baseline of the neuron gets disrupted.  For starters, it helps to know that neurobiologists decided to call a cell at resting potential (roughly -70 mV) “polarized,” so any change in the opposite direction, that is, toward a positive potential, is depolarization.  It also turns out that at rest, the cell has a higher inner potassium concentration than outer, and vice versa for sodium.  The way I remember this is that since the chemical symbols of sodium and potassium are Na and K, respectively, it’s as if sodium says “Nah” to the cell and so it mostly goes outside, while the potassium says “Kay” and stays in.

Sounds dumb, but you’ll remember it, and that’s what matters.

Let’s extend that party analogy to action potentials and see if it doesn’t make you hate the concept of parties.

Recall that we said sodium ions were the relatively immobile drunkards at this scene of debauchery, who could not easily open the door between rooms A and B, while potassium ions were sober and crossed over with ease.  Because of a combination to attraction to the music in room A and repulsion from each other’s sweat-drenched meatbags, these two groups of people settled into an equilibrium.

You might be wondering why the sober people would tend to stay more in A and drunks in B.  Well, that’s all thanks to our friend, the sodium-potassium pump.  Let’s call him Drake.  He’s sort of an intra-party bouncer.  He doesn’t want to completely kick out the drunks because they’re not puking on anything.  But they’re making fools of themselves enough by singing obnoxiously in room A that Drake figures the rest of party would thank him if he kept most of them out of there.  Every once in a while, some sober people will drift out of A as drunks wander in, but Drake responds to this by bouncing some drunks into B and sober folk into A.

Now, since Drake really wants to do a favor to those in room A who don’t want to hear tone-deaf renditions of “Hot in Herre” at 120 decibels, he kicks out 3 drunks for every 2 sober people he brings in.  This frees up a little space in A for someone to wander from B back to A, and this person might be either drunk or sober – in terms of concentration, a drunk person is more likely because of Drake’s bouncing, but also, remember, drunks can’t open doors so easily.  It’s hard to say what exactly will happen, but on the aggregate, as Drake does his thing, the imbalance in drunk vs. sober concentration in these two rooms will become established along with the imbalance in total population caused by the music, mentioned above.  The actual sodium-potassium pump, of course, doesn’t exchange 3 sodium ions for 2 potassium ions out of a sense of purpose.  Rather, this protein expends some chemical energy to make this exchange simply because of the affinities of these ions for the protein in its “in” and “out” conformations.  The exact physics of this is more complicated, but not super relevant to this larger idea.

If this were the whole story, the neuron/party would be a little more dynamic, but not terribly interesting.  Let’s throw another wrinkle in.  This is where the analogy is going to get a bit…forced…but bear with me.

It turns out there isn’t just one doorway between A and B.  A few of these are regular ol’ doors – mostly drunk-proof.  In a neuron, the physical significance of this distinction is just that there are more and “wider” channels through the membrane that can allow potassium to pass, than sodium.  Some are guarded by Drake and his clones.

Others are passageways without actual doors, but there’s some vomit on the floor at each of these passageways.  So not only can drunks get through because they don’t need to turn doorknobs, but in fact only drunks will go through these since they’re beyond the point of being grossed out by a puny pool of vomit.  However, besides Drake, this party has a few other internal bouncers who stand around these doorways – hence these doorways represent channels that only let sodium through, but they are closed even to sodium when the membrane potential is very low (including at baseline) or very high (above roughly +40 mV).  Normally, they can keep the drunk people out of A pretty well, but suppose that when the group in A gets unusually large (i.e. the potential gets higher, less negative because more positive ions are inside the cell), the drunks in B get particularly desperate to join them out of a strong sense of FOMO.  So they barrel through the guards, come hell or high water.  Some voltage-gated sodium channels have opened.

There’s a positive feedback loop that can result here!  If some drunk folk burst through one passage and the crowd swells more, the others in B are going to want to join in even more (translation: the cell’s potential gets even less negative because of the influx of sodium ions that more channels open).  They break through too.

Room A gets boppin’.  This is a state of extreme depolarization.

For this to happen, however, the trigger that caused the mowing down of the first poor guard needs to be significant enough (i.e. consist of a large enough influx of positive charge, from whatever source) to counteract another force, namely, the outward flux of sober people/potassium.  These folks aren’t as concerned as the drunks are about joining a massive group for that sweet, sweet collective effervescence.  If the population of room A swells, they’re going to rush out (by the same forces of repulsion that we discussed in examining the source of the resting membrane potential).

Suppose there are some doors with locks – totally drunk-proof, but also the sober people won’t bother using these doors to get through unless they’re in a particular hurry to leave a very overstuffed room A.  These are voltage-gated potassium channels – analogous to the sodium ones, except these open when potential gets very high rather than close.  Importantly, the potential doesn’t have to be that high for these channels to stay open, only to start opening.  They close at exceptionally low potential.  How exactly this occurs physiologically is complicated, and beyond the scope of this post.

So, if for whatever reason a small group of people are in room A beyond the usual baseline, some drunks might rush in, but some sober people will also rush out through the regular doors.  They don’t have to overcome the resistance of any guards, so under these circumstances, the sober outflow will win out over the drunk inflow, and room A will reach baseline, so that the drunks left in B won’t bother trying to knock down the guards to follow suit (let’s suppose the guards can pick themselves up reasonably fast).  The only difference in outcome here is that there are comparatively more drunk people in A than before, and more sober people in B.  Drake will take care of that.  This is a “failed initiation,” a case in which the stimulus of added positive charge to the neuron is too weak to cause an action potential.

For any bump in population of room A below a certain threshold (this is assuming drunk humans are more deterministic beings than they actually are, but hopefully it gets the point across), this restoration of the natural order will occur.  Nothing special.

But if that bump is above the threshold, it’s raining drunks.  Positive feedback does its thing, as described above, and room A just keeps getting more and more stuffed (depolarized by a massive influx of sodium) until two things happen.

On one hand, the guards get steamrolled by the drunks to such a pitiful degree that they call out for reinforcements, and the doorless doorways get blocked completely by these helpers.  No more drunk people are getting into A, period – the voltage-gated sodium channels have reached their upper limit of the window in which they’d stay open.  Critically, once these channels close at this limit, there’s a stretch of time in which they won’t open up again no matter what, not even if the potential dips below that limit again.  It’s as if the reinforcements at the doorway keep watch to make sure things have cooled down.  This is called the absolute refractory period.

On the other, the awful drunk singing and crammed space is sufficiently unbearable in the packed room that the sober folk find the keys to the locked doors and haul ass en masse from A to B.  Such is the opening of voltage-gated potassium channels.

So now room A gets continuously depopulated (drunks mostly can’t come in to counterbalance the outflow of sober people, recall), and this keeps going until the sober people find the circumstances in A tolerable again.  Notably, that point is when the population of A is below baseline (this is called hyperpolarization), since in this rush where many doors are open to the sober folk, they just keep exiting until there’s plenty of comfortable space in A (that is, until the potential is sufficiently low that the voltage-gated potassium channels close).  Physically, hyperpolarization is just a result of the relatively large permeability of potassium through the membrane, while sodium barely passes through at all by comparison.

It’s at this point that the absolute barrier posed by the guards at the doorways breaks down, since most of the drunks are inside A anyway and the guards figure that the coast is clear.  Some guards remain, but they are as vulnerable to a rush of drunkards as before.  That is, the voltage-gated sodium channels remain closed, but they are capable of being reopened now, and the absolute refractory period ends.  As time goes by, the frantic nature of this sober exodus dies down, and people begin trickling back into A because the music is still pretty nice, until baseline is achieved once more.  Before that baseline is reached, it would take an even greater disturbance (depolarizing stimulus) to trigger another action potential than in the initial case.  Hence we call this window between hyperpolarization and the resting membrane potential the relative refractory period.

And there you have it.  That’s the cycle, in all its glory.  I use that word half-facetiously, but it really is an elegant process in my opinion.  I hope you agree.

Now let’s see if we can use this knowledge to interpret the paper I seem to have forgotten about in this post…

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