Genetic Alteration of Phospholipase C Beta-3 Expression Modulates Behavioral and Cellular Responses to Mu Opioids

Xie, W. et al. (1999). PNAS 96: 10385-10390.

Lipids and opioids...is there a connection?  Apparently, according to this paper!  Now, this really isn't too surprising since opioids bind to opiate receptors in the brain, which can then modulate lipids via phospholipase C-beta.  Okay, did I lose you there?  Let me back up a bit...

Opiate receptors are at the cell surface and bind to endogenous opioids (like endorphins or enkaphalins), but they can bind to exogenous opioids as well (like opium, or its active ingredient, morphine).  When then bind their ligand, the receptors become activated and then send a signal down into the cell via different proteins.  One of these proteins that gets activated by the opiate receptors is phospholipase C-beta (PLC-beta).  This is an enzyme the cleaves particular phospholipids (lipids with phosphate groups attached, the one cleaved by this enzyme is PIP₂, or phosphatidylinositol-4,5-bisphosphate...whew!), one cleavage product (called IP₃, or inositol-1,4,5-trisphosphate) can then go into the cell to release intracellular calcium (which then goes on to activate various proteins) while the other cleavage product (called DAG, or diacylglycerol) stays at the membrane to activate other proteins (like PKC).  Okay, enough already, right?  No problem, I just wanted to explain the pathway from opiate receptors to the signaling through lipids so you understand that this connection has already been made and characterized.

If this is the case, what's the big deal in this paper?  Well, the authors generated "knockout mice" (mice genetically engineered to lack a specific gene) that are deficient in one isoform of the PLC-beta family: PLC-beta3.  When they then tested these mice to opiates, they found that they were much more sensitive to the analgesic properties (that's why morphine is used in hospitals, right?  Because it's an analgesic and helps alleviate pain) than normal mice.  Further, the cellular responses reflected the behavioral responses: cells from the knockout mice were much more sensitive to these opioids than cells from normal mice.  All in all, this suggests that PLC-beta3 works to inhibit opiate-mediated responses!

Now, you may be thinking..."So, what does this have to do with me?"  I think a good word to introduce here is "pharmacogenetics".  What is this?  Well, it's the idea that genetics plays an important role in the response to different drugs.  Basically, if you look around you, you'll notice that we are not genetically identical (unless you're one of the few number of identical twins).  Because of this genetic variability, we may have different sensitivities to the actions of different drugs.  One person may be much more sensitive to a particular drug used to treat his/her disease and require a lesser dose, or another person may require a higher dose to achieve the desired effect.  Thus, drug therapies may have to be tailored to the individual based on their genetic makeup...that's pharmacogenetics!

So, a person with a mutation in PLC-beta3 may be much more sensitive to opiates that normal people (according to the above paper).  That might mean that (1) this person may be more prone to develop an opiate addiction (for example if they were to try heroin), and/or (2) this person may require a much lower dose of morphine when they're in the hospital.  Thus, if we understand the genetic influences on drug responses, we can watch out for this and be better prepared.  This field is just beginning to blossom (understanding how genetic factors play a role in drug responses), so be sure to keep your eyes open for new and exciting research in this area! 

Okay, thanks for visiting this site and I hope you enjoyed this little summary!  Be sure to check back soon for new advances!  Thanks again!