The neuropharmacological brilliance of the meningococcus

The meningococcus can kill you within 12 hours after the spots appear — https://en.wikipedia.org/wiki/Waterhouse–Friderichsen_syndrome.  Who would have thought that it would be teaching us neuropharmacology.   But it is —  showing us how to make a new class of drugs, that no one has ever thought of.

One of the most important ways that the outside of a cell tells the inside what’s going on and what to do is the GPCR (acronym for G Protein Coupled Receptor).  Our 20,000 protein coding genome contains 826 of them. 108 G-protein-coupled receptors (GPCRs) are the targets of 475 Food and Drug Administration (FDA)-approved drugs (slightly over 1/3).   GPCRs are embedded in the outer membrane of the cell, with the protein going back and forth through the membrane 7 times (transmembrane segment 1 to 7 (TM1 – TM7). As the GPCR sits there usually the 7 TMs cluster together, and signaling molecules such as norepinephrine, dopamine, serotonin etc. etc. bind to the center of the cluster.   This is where the 475 drugs try to modify things.

Not so the meningococcus. It binds to the beta2 adrenergic receptor on the surface of brain endothelial cells lining cerebral blood vessels, turning on a signaling cascade which eventually promotes opening junctions of the brain endothelial cells with each other, so the bug can get into the brain.  All sorts of drugs are used to affect beta2 adrenergic receptors, in particular drugs for asthma which activate the receptor causing lung smooth muscle to relax.  All of them are small molecules which bind within the 7 TM cluster.

According to Nature Commun. vol 10 pp. 4752 –> ’19, the little hairs (pili) on the outside of the organism bind to sugars attached to the extracellular surface of the receptor, pulling on it activating the receptor.

This a completely new mechanism to alter GPCR function (which, after all,  is what our drugs are trying to do).  This means that we potentially have a whole new class of drugs, and 826 juicy targets to explore them with.

Here is one clinical experience I had with the meningococcus.  A middle aged man presented with headache, stiff neck and fever.  Normally spinal fluid is as clear as water.  This man’s was cloudy, a very bad sign as it usually means pus (lots of white blood cells).  I started the standard antibiotic (at the time)  for bacterial meningitis — because you don’t wait for the culture to come back which back then took two days.  The lab report showed no white cells, which I thought was screwy, so I went down to the lab to look for myself — there weren’t any.  The cloudiness was due to a huge number of meningococcal bacteria.  I though he was a goner, but amazingly he survived and went home. Unfortunately his immune system was quite abnormal, and the meningitis was the initial presentation of multiple myeloma.

What neuropharmacology can’t tell us about opiates and addiction

A friend’s wife had some painful surgery and is trying to get by with as little opiates as possible, being very worried about becoming an addict, something quite reasonable if all she had to go on was the popular press with lurid stories of hapless innocents being turned into addicts by evil physicians overprescribing opiates (it’s the current day Reefer Madness story). Fortunately her surgeon wisely told her that her chances of this happening were quite low, since she’d made it past 50 with no dependency problems whatsoever. Here’s why he’s right and why neuropharmacology can’t tell us everything we want to know about opiates and addiction.

Back in the day, disc surgery required general anesthesia, dissection of the back muscles down to the spine, sometimes chipping away at the bones of the spine to remove a bone spur (osteophyte) and/or removal of the offending herniated intervertebral disc. This meant a hospital stay (unlike my ophthalmologist who had a microdiscectomy as an outpatient a few years ago). This was the era of the discovery of the protein receptor for morphine and other opiates, and we were all hopeful that this would lead to the development of a nonAddicting opiate (narcotic). Spoiler alert — it hasn’t happened and likely won’t.

Often, I was the neurologist who diagnosed the disc and told the surgeon where it was likely to be found (this was in the preCT and later the preMRI era). I’d developed a relationship with most of those I’d referred for surgery (since it was never recommended, without a trial of rest — unless there were compelling reasons not to — trouble controlling bowels and bladder, progressive weakness etc. etc.). I was their doc while they tried to heal on their own.

So post-operatively I’d always stop by to see how the surgery had worked for them. All were on a narcotic (usually Demerol back then) as even if the source of their preoperative pain had been relieved, just getting to the problem had to cause significant pain (see above).

If the original pain was much improved (as it usually was), I’d ask them how they liked the way the demerol made them feel. There were two types of responses.

#1 I hate feeling like this. I don’t care about anything. I’m just floating, and feel rather dopey. I’m used to being in control.

#2 I love it ! ! ! ! I don’t have a care in the world. All my troubles are a million miles away as I just float along.

Love it or hate it, both groups are describing the same feeling. Neuropharmacology can help to tell us why opiates produce this feeling, but it can’t tell us why some like it (about 5%) and the majority (95%) do not. This clearly is the province of psychology and psychiatry. It’s the Cartesian dualism between flesh (opiate receptor) and spirit (whether you like what it does). It also shows the limitation of purely physical reductionism of the way we react to physical events.

The phenomenon of a small percentage of people becoming addicted to a mind altering substance is general and is not confined to one class of drug. We were told never to prescribe chronic benzodiazepines (valium, etc. etc.) to a recovered alcoholic. People who get hooked on one thing are very likely to get hooked on another.

I realize that some of this could be criticized as blaming the victim, but so be it. Medical facts are just that, like what they say or not.

Addendum 11 Sep ’16 — I’m not saying that you won’t become physically dependent on opiates if you get them long enough and at high enough doses. We all would. Even if this happened to you. When you no longer needed them for pain and went through medically supervised withdrawal, you wouldn’t crave them, and do crazy things to get them (e.g. you were physically dependent but never addicted to them — it is important to make the distinction).

Example — when I was in the service ’68 – ’70, we had half a million men in Vietnam. Everyone I’ve talked to who was over there says that heroin use among the troops was 25 – 50% (high grade stuff from Thailand was readily available). As soon as they got back to the states, the vast majority gave them up (and with minimal withdrawal requiring my attention – I think I saw one convulsion due to withdrawal).