We have previously described a novel opioid agonist, termed herkinorin, that activates mu opioid receptors without recruiting ?arrestin2. ?arrestins are involved in desensitizing and regulating opioid receptors and the removal ?arrestin2 in mice increases morphine's analgesic potency while attenuating morphine tolerance. Mice that lack ?arrestin2 also display significantly reduced morphine-associated side effects, such as constipation and respiratory suppression. Therefore, the development of a ligand that could activate the mu opioid receptor, but not invoke the ?arrestin2 interaction, may pharmacologically recapitulate the effects of morphine in ?arrestin2 knockout mice. Such compounds would ideally produce analgesia with very limited tolerance or side effects. Opioid tolerance has been associated with the desensitization of the mu opioid receptor. One would predict that in the absence of ?arrestins, the MOR would not be desensitized. However, chronic herkinorin treatment in cells leads to a desensitized MOR. This proposal has been developed to assess whether that desensitization is due to protein kinase C-dependent regulatory mechanisms as these kinases have been previously shown to regulate mu opioid receptor responsiveness. Further, we will directly test whether herkinorin will lead to analgesic tolerance in mice. Such studies are necessary to determine the feasibility of developing opioid agonists that do not recruit ?arrestins to promote analgesia in the absence of tolerance and side effects. The Public Health Relevance: Our studies are designed to explore the feasibility of designing new opioid analgesics that we predict will produce less analgesic tolerance and limited side effects such as constipation and respiratory suppression. We will base our studies on a lead compound that we have recently described;this compound has very promising biochemical properties that would lead us to predict it would possess these favorable characteristics.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Small Research Grants (R03)
Project #
5R03DA025259-02
Application #
7851235
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Lin, Geraline
Project Start
2009-06-01
Project End
2011-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
2
Fiscal Year
2010
Total Cost
$97,250
Indirect Cost
Name
Scripps Florida
Department
Type
DUNS #
148230662
City
Jupiter
State
FL
Country
United States
Zip Code
33458
Raehal, Kirsten M; Schmid, Cullen L; Groer, Chad E et al. (2011) Functional selectivity at the μ-opioid receptor: implications for understanding opioid analgesia and tolerance. Pharmacol Rev 63:1001-19
Bohn, Laura M; McDonald, Patricia H (2010) Seeking Ligand Bias: Assessing GPCR Coupling to Beta-Arrestins for Drug Discovery. Drug Discov Today Technol 7:e37-e42