I’m back… time to leave again

Well, aside from the lack of internet access the Cayman Pain Meeting was a big success.  I have been to this meeting several times and it never disappoints.  There were 6 days of talks and about 30 sessions with more than 100 speakers.  Each speaker gave a ten minute talk with 5 minutes for discussion.  Nearly every talk was about the latest findings (so mostly unpublished work) from the lab of the PI or the latest work of the postdoc (yes, several postdocs gave talks).  Following the morning sessions we had time to get together and talk science and I had the opportunity to meet several junior PIs at a variety of institutions who are getting some exciting research projects off the ground.  All in all, despite the funding problems we are all experiencing, these are exciting times for the pain neuroscience field.  Below are some of the major themes that emerged from the meeting…. 

1) Cannabinoid pharmacology is a mess that needs some cleaning. Many of you probably know that cannabinoids provide analgesia but the mechanisms for this, particularly in the periphery (outside the CNS), are very controversial. A concept was proposed at the meeting that I think has much potential to make some sense of all the confusion. Cannabinoids are generally agonists of the cannabinoid GPCR receptors, CB1 and CB2; however, many of these same compounds have agonist or antagonist activity at TRPV and TRPA channels. The proposal was that the pharmacology of cannabinoids should be organized considering GPCR (or metabotropic receptors) and ion channels (namely TRPV1 and TRPA1) and that in order to consider a given compound as selective they should be screened for agonist and ANTAGONIST activity at TRP channels. In other words, it is difficult or impossible to interpret your findings unless the pharmacology at ionotropic cannabinoid receptors is known. I wholeheartedly agree and hope that the field starts paying more attention to these details. We now know enough about these pharmacological interactions to do this sort of work with new compounds and gaining a better understanding of these mechanisms will advance the field greatly.

2) TRPA1 pharmacology is hot! All sorts of environmental pollutants activate the channel as do many endogenous electophilic compounds. In addition to TRPA1s role in pain it is becoming clear that it may play a major role in asthma, cough and a variety of other respiratory conditions that we encounter on our polluted earth. If I ran a big pharma (and I don’t) I’d be dumping all sorts of resources into this area, opportunities abound.

3) The picture of microglia’s role in neuropathic pain is becoming quite clear. The different pathways that initiate and maintain microglial activation after a nerve injury were talked about by several groups and the data more or less fit a model that was eventually proposed in one the later sessions. It will be interesting to see how well the model holds up to further scrutiny but I left the meeting with the impression that the field is heading toward having a fairly clear picture of what is going on and that some quality intervention points are being elucidated for therapeutics.

4) The role of ATP in skin and organ communication with pain sensing neurons (nociceptors) is rapidly becoming a hot area for a number of pain conditions. ATP-sensing channels (mainly P2X3) have been a hot area for some time but the mechanisms of ATP release and sensing by these channels are just starting to become clear. Expect some big findings to come out in the coming months/years in this area with major relevance for pain conditions like CRPS (complex region pain syndrome).

5) Researchers in the pain field genuinely like each other. I’ve been in the pain filed for quite some time now and I continue to be struck by how well everyone gets along. We had a few contentious debate periods during the conference, particularly in my session, but they were all cordial and respectful. I think this is a major plus because it encourages people to speak up and have their say without being intimidated or being afraid of unfair reprisals. Several outstanding debates broke out in my midst after the sessions and I think some important advances were made as a result. The format of the meeting (morning talks with afternoon off) also helps to facilitate this sort of activity. Moreover, most PIs stuck around for the entire meeting (a whole week) so you didn’t have to corner anyone to get a chance to speak with them. Overall, a perfect setting for someone like me trying to establish myself as an independent researcher in the field.

Finally, I have to give props to Mike Salter (the only name I will name here) who did a truly amazing thing during the conference (Mike is a big fish in the pain field and in NMDA receptor mechanisms). Anyone who knows Mike probably already thinks he’s a great guy, but I’ve gotta tell you, he made an impression on me at the meeting that I will never forget. Mike gave a talk on the second to last day on one of his projects. Apparently, the night before, he had dinner with a postdoc from France who told him about some data she had on a topic that was pioneered by work from Mike’s lab. Rather than scooping her, as I’m sure he could, he decided the best thing to do was to promote this young researcher’s work at the conference (she had not been invited to speak). When Mike got up to talk he spoke for about a minute and then called her up to the stage to present her work (a talk within a talk). That night and morning Mike had helped her get her slides together and put them into his talk. She got up on stage and talked for about 5 minutes about her data. She blew all of us away with a simple and elegant set of results that might just have been the most intriguing pieces of data presented at the entire meeting. Following her talk, Mike spoke very briefly about the work of another postdoc in his lab who had data that also supported the model they are working on. So, in 10 minutes, Mike managed to promote the hard work of two outstanding young scientists (one who he met the evening prior) within the context of an important area of the microglial interaction with the CNS in neuropathic pain. I think I speak for the whole crowd in saying that I couldn’t have been more impressed.

So, now I have a pile of work sitting in front of me from being away for a week and I have to go to the American Pain Society Meeting in Tampa on Wed morning. Very busy times! Good news is that there is free Wifi in the Tampa convention center so look forward to some live blogging from Tampa APS!

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8 responses to “I’m back… time to leave again

  1. And don’t forget about the notorious CB3, the lurker cannabinoid. I think it’s real.

    That’s a great story about Mike Salter–he sounds like a tremendous force for good!

  2. I spent more than a year of my PhD trying to clone that darn CB3. What about GPR55? Does that one qualify as CB3? The real question is, what is the endocannabinoid transporter mechanism? Protein, intrinsic property of lipid, something else altogether? Who knows, but one thing is certain, your efforts will most likely lead you directly to FAAH, one way or another.

    Mike is a force for good, until you get to the bar, where he destroys us mortals.

  3. The proposal was that the pharmacology of cannabinoids should be organized considering GPCR (or metabotropic receptors) and ion channels (namely TRPV1 and TRPA1) and that in order to consider a given compound as selective they should be screened for agonist and ANTAGONIST activity at TRP channels.

    transl: we pain d00ds want to ignore the fact that the central dominating theme of cannabinoid science for literally tens of thousands of years is the psychoactive effects because we’re, er, interested in pain. everything must be reconceptualized to fit with our worldview.

    JP, other neurotransmitter systems have plenty of complexity and it ain’t the end of the world to limp by on “well, maybe it is a neutral antagonist but really it is an inverse agonist” arguments and qualifications. “selective” has always been a relative and eyes-of-beholder concept anyway. in short, nothing special here.

  4. Hey BM, I don’t agree at all.

    First off, there is ample evidence that the first uses of cannabinoids in China (tens of thousands of years ago) were associated with an analgesic use. Same story in India. Moreover, there is emerging evidence that some of the effects of cannabinoids in the brain are mediated by TRPV1 (like the recent LTD paper in Neuron). Many previous interpretations based on CB1 antagonists are turning out to be related to TRPs because these same antagonists are also antagonists at TRPV1/TRPA1. Just saying that we know more now and we can do much, much better in defining our pharmacology. After all, what is wrong with having metabotropic and ionotropic cannabinoid receptors? Finally, what about the evidence that TRP channels evolved far before CB receptors? What if some of those ancient channels turn out to be activated by lipid products of enzymes that are related to mammalian endocannabinoid synthetic enzymes?

  5. As Dr Hyde says, “Pharmacology is a crock.”

    I didn’t know that the various CB agonists or antagonists had TRP action, though….will be interesting to see how many results need reinterpretation!

  6. I am not arguing against your plea for better and more accurate pharmacological description of compounds in the literature. All I’m saying is that many, many compounds have complex pharmacology which people in one subarea or another chose to overlook or simplify for one purpose or another. We get along just fine without wholesale, handwringing, pedantic re-description of compounds each time a new paper comes out!

    there is ample evidence that the first uses of cannabinoids in China (tens of thousands of years ago) were associated with an analgesic use.

    I note you use the plural for “uses”, lol. And this is like saying alcohol was associated with analgesic use. Sure they were and are but c’mon, this is not the primary use in any way, shape or form.

    After all, what is wrong with having metabotropic and ionotropic cannabinoid receptors?

    nothing at all….did I say that?

    Finally, what about the evidence that TRP channels evolved far before CB receptors?

    and the evolutionary history of receptors is relevant to nomenclature why? I mean when you think about it the real absurdity is that we call it the “endocannabinoid” system as opposed to the “anandamidergic” system or some such.

    now what do you think about the much rumoured true neutral CB1 antagonist(s)? pipedream?

  7. Well, I would call it the 2-arachidonyl-glycerolergic system but now we are really splitting hairs. Either way, your points are well taken (and no, you didn’t say that). As for the true CB1 antagonists I am skeptical. There was a paper in Mol Pharm back in 2002 (I think) about intrinsic activity at CB1 that has had a long-standing impression on me concerning the possibilities of neutral antagonists at the receptor. On the other hand, I am aware of compounds that are in trials that apparently are really neutral antagonists but the data on this is not in the lit, so who knows (but my money would be on pipedream).

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