No break goes unpunished. I've been working to ensure the research progresses during my short absence, and we all know I'm coming back to an overabundance of work too. Regardless, the mental break and the brief respite from all the damn cat-herding will be incredibly welcome.

Enjoy your holidays (if you haven't already celebrated), kind readers, and we'll get back to some pharmacology when I return from a nice little location that has sand and water, seafood and good wine.

Thanks to everyone who contributed and commented on the relocations poll! I thought I'd graph up the data and share the responses.

There were n=48 respondents to the poll, and everyone answered both questions. Unfortunately, Polldaddy doesn't give me correlative results, so I don't have info for number of relocations broken down specifically by career stage. But it's something.

First question: How many relocations have you made for career or training reasons?

Figure 1. Number of relocations

Next question: what career stage are you in?

Figure 2. Current career positions

Looks as though most respondents fell into the 2-4 relocations range. However, there are a number of responses indicating more than 4 moves, including at least one "extraordinary" number. (Yikes!) Science is a demanding career, indeed. I wish I had asked how many of those moves were paid out of pocket vs reimbursed! On second thought, the results would probably be depressing.

The most common responses for career stage were 1st Postdoc and 1st Permanent position. (I'm not sure whether the prevalence of 2nd+ Postdoc should be disheartening, or encouraging in that "misery loves company" kind of way.) While we can't correlate due to the data limitations of polldaddy's free accounts, I think it follows the typical career track well to speculate that the 2-4 relocations range is likely associated with these career stages.

One thing I particularly liked is that people from many different places contributed to the poll. There were 12 countries represented among the responses! Awesome! It's always a plus to get a more well-rounded perspective on careers, as well as to see that my readers are not totally US-centric.

These results also let me feel a little more "normal" - at a time when basically my entire family is asking when I'm going to get a job closer to home (i.e. them) and quit my gallivanting around the country, this is particularly helpful.

I was pondering the number of major relocations I've made (and consequently, dragged spousal unit through as well) in the name of my scientific training and career development.

There was the first one, to go to college as far away from my hometown as physically possible without losing the in-state tuition benefit. (ok, there was more reason than this, and I adored my college years, but that was a damn compelling reason to start.)

Then a pretty big cross-country move to go to MegaU for grad school.

Next, another substantial relocation for my first postdoc position.

Finally, another long haul to wind up in my current position. I'm hoping we can settle down here for a while now. Though let me tell you, after all that, we are some experts when it comes to downsizing, packing, and methods for transporting goods and pets.

All this has me wondering. How many moves have YOU made for career- or training-related reasons?

And since my follow-up thoughts are more discussion and less surveyable, feel free to leave a comment about the following:
Was it exciting and enriching to see and do something new, or was it just a pain in the ass? Were spousal career issues affected? To what extent did this influence your career path?

Am I *ever* grateful for locally administered corticosteroids and local anesthetics right now.

I owe that to the many who have walked this way before me.

/just another day in the life

This is supposed to be the *twelve* months of Neurodynamics post, per the meme that's being passed around the blogs. I haven't been running this joint long enough to have twelve months of archives yet, so how about an abbreviated version?

August Welcome to the Neurodynamics blog! I’m Leigh, and I’ll be your tour guide.

September Last time, we got started with a discussion of stress reactions and brain adaptations.

October I've briefly mentioned the BBB and other extra barriers to drug permeability in a post about pharmacokinetics.

November This is one I have seen rising among my blog search term hits.

December Reader Abbe commented with a question about drug common pathways and interactions.

Reader Abbe commented with a question about drug common pathways and interactions.

In the book, The Science of Marijuana, Leslie L. Iversen, 2008, p. 56-57:
“Experiments with nerve cells in tissue culture or with thin slices of brain tissue incubated in the test tube have shown that the addition of THC or other cannabinoids can inhibit the stimulation-evoked release of various neurotransmitters, including the inhibitory amino acid GABA and the amines noradrenaline and acetycholine (Szabo and Schlicker, 2005).”

I have a question about GABA, the inhibitory neurotransmitter and cannabis. If I understand this correctly, cannabis inhibits GABA release. Less GABA in the system causes a whole raft of problems: increased muscle tension, anxiety, problems with sleep, and more.

I came off ten years of Ambien use for sleep issues. It was a living hell getting off this stuff. Ambien works on the same receptors as the benzodiazepines and artifically ups GABA in the body, which causes the body to stop producing so much GABA. Go off the stuff and you get serious withdrawals, and it can be life-threatening for some people. Their is a seizure risk when going of these drugs, tapering slowly is key to let the body start making more GABA.

Four months ago, I was given a medical marijuana recommendation by one of my doctors. I live in a medical marijuana state. So I started using cannabis for chronic myofascial pain. It worked great for a while, but now my myofascial pain has returned with a vengeance. I wonder if it’s because of cannabis’s effects on my GABA levels.

If cannabis is suppressing my GABA levels, I’m back where I was in the Ambien withdrawal cycle.

Any thoughts or comments?

Yes, Abbe! I have many thoughts and comments! I think we should start by looking at mechanisms of the drugs mentioned.

Abbe posted the question on my Pharmacology of Marijuana post, where I wrote that THC actions at CB1 receptors resulted in the suppression of neurotransmitter release at the presynaptic cell. This applies to GABA release in addition to several other neurotransmitters, just as Abbe quoted from the book she had read, so she is exactly right.

In the course of thinking about this question, I realized that I haven't written a post specifically on sleep drugs! Well, damnit. That's a very nice topic for a full drug mechanisms post. But since I'm answering a question here, I will keep it brief. Ambien, aka zolpidem, belongs to the sedative-hypnotics class of drugs. What this class of drugs does is dose-dependently reduce consciousness. In the case of the sleep drugs, this is accomplished by selectively enhancing the effects of GABA signaling at the GABA(A) receptor, a mechanism we call positive allosteric modulation. They do not act as agonists all on their own, the presence of GABA is required.

Like many other drugs, tolerance does develop after repeated use of zolpidem. Withdrawal can be a difficult thing to endure, especially if it is after such a long term treatment as Abbe describes. In response to the enhanced effects of GABA, GABA(A) receptors can desensitize and downregulate, just as I've discussed in previous tolerance posts. Upon removal of the allosteric modulator, this can lead to a more excitable state in the brain, as the cellular response to inhibitory signal is desensitized. Tapering the dose of drug down helps to allow the receptors to slowly re-equilibrate and re-establish signaling sensitivity before the drug is fully withdrawn from the system.

There is a component of zolpidem tolerance that results in a decrease in extracellular GABA presence in some brain regions. This is likely due to a feedback regulation mechanism- more homeostasis at work. Again, a taper-off withdrawal from a drug would do exactly as Abbe indicates- allow the system to re-equilibrate slowly rather than shocking it all at once, which can have nasty consequences when GABA modulation is involved.

Now, back to cannabis and GABA, and to consider this common link.

While having THC on board and acting in the brain does reduce GABA release from the subset of pre-synaptic terminals that do contain CB1 receptors, this is not nearly as universal of an effect as something that targets GABA receptors. To make this more clear, yes, there are a LOT of CB1 receptors, and they are spread around many parts of the brain. But not all GABA terminals contain CB1 receptors, and not every instance of GABA release is suppressed by THC. This is in contrast to the situation with sleep drugs that target GABA(A) receptors, which are pretty much universally present at GABA synapses.

So I don't think Abbe is experiencing the same phenomenon with her medical marijuana prescription as she experienced with the sleep drugs. While  related, they appear to me to be distinct pharmacological and homeostatic phenomena. Though with some particularly interesting links, and I really am impressed by Abbe's critical thinking and putting that together.

However. This leaves a big question mark as to why her pain returned so voraciously. Why might that be? Well, there are many, many possibilities, most related to the fact that we don't know nearly enough about pain. (Pain Research Matters!) However, one thing that immediately came to mind for me, as I speculated what might be going on, was the observation that sometimes marijuana can cause an increased sensitivity to pain.

I know- stop the presses. (1) Marijuana is not all good?! and (2) Unexpected effects of a prescribed regimen?!

The sarcasm is not meant in any way to deride Abbe or the unfortunate increase in pain she is experiencing- I principally wish to emphasize that we find the unexpected in everything. Everything.

Snark aside, I'm really serious here. First and foremost, tolerance happens. After four months, depending on the regimen used, there could be receptor-level adaptations in the pathways that mediate pain, resulting in a pain increase and inability of the marijuana dose to overcome that pain signaling regulation. Certainly possible, and there are lots of individual differences here. But let's branch away from the homeostasis stuff here. There are two studies that I thought of when considering an increase in pain during marijuana exposure. First one points to a possible dose effect, with low doses reducing pain and higher ones having the opposite effect. THC has shown to produce biphasic effects in anxiety, for one- low doses typically produce a reduction, high doses an increase. It's possible this is part of the story. The next observation describes a potential mechanism for cannabinoid-driven pain sensitization. While a fascinating paper, even I find it a bit heavy to digest and would like to see further experiments. (When folks write for the glamorous journals, they have little space and lots of data. This usually annoys me and does not usually reduce the amount of time it takes me to understand wtf they did!)

Obviously, the clinical data we have to work with come with their own set of limitations, and a given individual's case might not reflect any one distinct observation we have available to us. In short, we know precious little about the instances and mechanisms of increased pain during marijuana use, but we have a couple of footholds and hopefully roads toward a better understanding. I suspect it's the combined effect of THC upon a diverse set of synapses, perhaps the dose regimen or term of use, and probably some differential tolerance (by type of synapse or by brain region or something else I haven't thought of yet). But that's just my wild speculation at this point, as we have no solid data.

Abbe, I thank you for what is probably the most fascinating reader question I've encountered so far. I hope I've been able to give you some more to think on as you move forward. I wish you the best of luck!