Seminar: Mutant Mu-Opiod Receptors and Pain Management

On May 3^rd, I had the opportunity to attend Elizabeth Pearsall’s thesis presentation entitled: Molecular Mechanisms of Mutant Mu Opioid Receptors (MOR) where Naloxone, an Inverse Agonist, Acts as an Agonist and Relieves Pain . The purpose of her dissertation was to shed light on the 100 million Americans who suffer from chronic pain, a population of people that totals more than all other conditions combined (diabetes, heart disease etc.). Consequently, pain management is an aspect that has caused difficulty for those individuals who experience chronic and acute pain on a daily basis. Although there are painkillers available now for such patients, these medications include many unavoidable side effects such as, respiratory depression, gastrointestinal problems like constipation, as well as dependence, addiction, and withdrawal symptoms. Therefore, Pearsall and Dr. Reggio’s lab focused on the mu-opiod receptor agonist (morphine) and its sister drugs such as codeine, oxycodone etc. in efforts to discover the mechanism of a mutant mu-opioid that managed pain with less tolerance and withdrawal than the current market drugs.

            In fact, there are three types of opioid receptors, including delta and kappa. However, only mu agonists produce analgesic effects. Pearsall, used Naxolone, a drug used in the contest the effects of drug overdoses, to study its molecular mechanism as a full agonist and a partial agonist. It was important to note that in its regular form, Naxolone acts an antagonist, defined as a receptor drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses*. Essentially, as a single mutant MOR, Naxolone preformed as a partial agonist, whereas in the triple mutant form (TMT), Naxolone acted as a full agonist. As an agonist, Naxolone, therefore, takes on a different task than its original function, instead binding to a cell receptor and directly triggering a response by that cell.

            Experimentally, the mutant MOR of naxolone was injected into mice between their vertebrae and spine via a targeted-gene therapy strategy. The effects were quite ground-breaking, providing localized pain management for the mice for 8 weeks! The localization of the pain management was pivotal, in that, if an individual needed another drug elsewhere in the body, the MOR would not interact with it. Whereas, in a drug with systemic effects, another drug introduced to the body could possibly produce counter effects or cause a harmful/deadly interaction. If you want to read up on more about Naxolone and strides towards pain management, check out these cited sources below.

*www.fda.gov/drugs

1.         Chen, S. L.; Ma, H. I.; Han, J. M.; Tao, P. L.; Law, P. Y.; Loh, H. H., dsAAV type 2-mediated gene transfer of MORS196A-EGFP into spinal cord as a pain management paradigm. Proc Natl Acad Sci U S A 2007, 104 (50), 20096-101.

2.         Kao, J.; Chen, S.; MA, H.; Law, P. Y.; Tao, P. L.; Loh, H. H., Intrathecal delivery of a mutant Mu-opioid receptor activated by naloxone as a possible antinociceptive paradigm. The Journal of Pharmacology and Experimental Therapeutics 2010, 334 (3), 739-45.

3.         Claude-Geppert, P. A.; Liu, J.; Solberg, J.; Erickson-Herbrandson, L. J.; Loh, H. H.; Law, P. Y., Antagonist efficacy in MORS196L mutant is affected by the interaction between transmembrane domains of the opioid receptor. J Pharmacol Exp Ther 2005, 313 (1), 216-26.