Thread by @UTDPainLab

BOOM!! BOOM and BOOM! cell.com/cell/fulltext/…

Had a chance to read in detail this morning, and oh boy do I love this paper! While depression research and MOA of antidepressants are not really my thing now, the whole paradox of how the so-called SSRIs work is a major reason that I got into neuroscience to begin with.

First learned about this in neuropharmacology class as an undergrad @UT_Dallas in 1996 or so from a chapter in Basic Neurochemistry written by Alan Frazer and Julie Hensler. I was captivated by this paradox and decided to apply to @UTHealthSA #Pharmacology for grad school.

I got in and had every intention of working on this problem in Alan Frazer's lab. Did a rotation in his lab working with Lynn Daws just as she was transitioning to running her own lab. It was a great experience, but ultimately my rotation with Chris Flores lured me to pain.

But kept following this anti-depressant MOA story over the years with no really satisfying answers ever emerging in the literature. Of course the whole ketamine story emerged from @LisaMonteggia's lab which made the whole story so much more interesting to follow!

And I have to say that for me, this paper ties everything I think I know about this just beautifully. Obviously much more work is needed in this area, but this is really so exciting from a pharmacological mechanism perspective. It also finally gives something to target...

... from a drug design perspective. The interactions shown in the paper are not particularly high affinity, so presumably this could be dramatically improved with a real drug development campaign against this new binding pocket on TrkB. Which brings me back to pain!

For many years I have been perplexed at why ketamine and/or norepi transport blockers aren't better at inhibiting pain than they are. Well, now we have a potential mechanism. TrkB is great for enhancing plasticity, which includes enhancing dorsal horn pain transmission.

In fact, it might be better than anything else in doing this (@mikehildebrand7 what do you think?). If we can dial out the TrkB enhancing activity in norepi transport inhibitors I imagine that these could be dramatically improved pain drugs.

Moreover, one would imagine that tweaks to ketamine could be achieved that could create a very good spinally acting analgesic that could be far more efficacious, in particular for acute pain after severe injury.

One final thought in praise of rotations - I only worked with Lynn Daws, Alan Frazer and Julie Hensler for 3 months, but they all have had a huge impact on my career. 20 years later I am still eternally grateful that I had the chance to work in their group.