Opioids are the most efficacious compounds in the treatment of moderate to severe pain. However, with chronic use, many adverse effects including tolerance and dependence development will result. Differential tolerance development between the analgesic and respiration depression responses decreases the therapeutic index of opioids during chronic administration, which is a major concern. In order to overcome this obstacle, the holy grail of opioid research has been the development of an ideal analgesic, i.e., one that has minimal side effects, including tolerance and dependence development. Instead of developing specific orthosteric ligands that will activate a single receptor regardless of the oligomeric state of the receptor, we have pursued a novel approach to develop an opioid receptor mutant that can be activated by the opioid antagonist. This approach was based on our accidental discovery that mutation of Ser196 residue in the 4th transmembrane domain of mu-opioid receptor (OPRM1) results in the ability of opiate alkaloid antagonists such as naloxone and naltrexone to activate the receptor, without altering ligand afinity or agonist activity. This antagonist activity was demonstrated in vivo with a S196A knock-in mouse line and also with the adenoassociated virus- mediated delivery of the mutant receptor to various sites of the pain pathway. Importantly, chronic administration of naloxone in activating this mutant receptor does not result in tolerance development. The success of the OPRM1 mutant leads us to hypothesize that there must be allosteric modulators that can convert OPRM1 into conformations similar to that converted by the S196A mutation. We term such modulators as antagonist to agonist modulators or AAMs. The """"""""proof of concept"""""""" for the existence of AAMs activity was established by our recent identification of 10 probable """"""""hits"""""""" in our screens of 50,000 compounds in a library using a cell-based assay. Encouraged by these observations, we propose to (1) continue our screens of a chemical compound library for the existing of additional AAM activities;(2) validate the AAM activity in the identified """"""""hits"""""""" with other OPRM1 activity measurements, such as inhibition of adenylyl cyclase activity, induction of K+ current via activation of GIRK channels, and activation of ERK1/2. Studies to demonstrate that the """"""""hits"""""""" are actual allosteric modifiers of OPRM1 will be carried out also;and (3) to test for in vivo AAM activity by measuring the antinociceptive activity of the OPRM1 antagonist naloxone in the presence of such """"""""hits"""""""". The current proposed studies will be the initial steps in our development of allosteric modulators for OPRM1, and will validate our hypothesis that there is a new class of allosteric modulators, AAMs. AAMs will represent a novel class of drug molecules that can limit tolerance development during chronic opioid administration, thereby maintaining the therapeutic index of the opioid analgesic treatment paradigm.

Public Health Relevance

The need for opioid analgesic agents that can be used in chronic pain treatment with minimal side effects is rising. Our approach is to combine an antagonist that interacts with the receptor binding site with another ligand that binds to a different area of the receptor, thereby activating the receptor involved in pain control while inactivating other receptors involved in chronic effects such as tolerance development.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Exploratory/Developmental Grants (R21)
Project #
Application #
Study Section
Special Emphasis Panel (DDNS)
Program Officer
Rapaka, Rao
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Minnesota Twin Cities
Schools of Medicine
United States
Zip Code