The cloning of opioid receptors has advanced the neurobiology of opioid drug abuse but it is still unclear why agonists for the mu-receptor have a high potential for addiction while agonists for the kappa-receptor are aversive. All three opioid receptor subtypes are substantially homologous and are linked to identical second messenger pathways and ionic channels. However, opioid receptors can be pharmacologically distinguished from one another and each receptor can mediate unique physiological actions. One hypothesis to explain why opioid receptors mediate different physiological actions is their unique anatomic location results in the receptors' different effects. A genetic approach will be used to express one receptor subtype in place of another to determine if one receptor subtype can substitute functionally for another in vivo. A gene """"""""knock-in"""""""" will be performed to replace the mu-receptor exons with the kappa-receptor exons in the mouse by using the double-replacement technique. These mutant mice will then be tested to determine if kappa-agonists mimic mu- agonists in experiments examining behavioral reinforcement to opiates, opiate dependence, opiate analgesia, and tolerance to opiates. These experiments will determine if a specific intracellular signalling pathway coupled to the mu-receptor leads to drug addiction or if drug addiction is related to activation of specific anatomical pathways in the mouse brain.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32DA005841-02
Application #
2824536
Study Section
Human Development Research Subcommittee (NIDA)
Project Start
1998-10-13
Project End
Budget Start
1998-10-13
Budget End
2000-12-12
Support Year
2
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Oregon Health and Science University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
009584210
City
Portland
State
OR
Country
United States
Zip Code
97239
Appleyard, Suzanne M; Hayward, Michael; Young, Juan I et al. (2003) A role for the endogenous opioid beta-endorphin in energy homeostasis. Endocrinology 144:1753-60
Mogil, J S; Grisel, J E; Hayward, M D et al. (2000) Disparate spinal and supraspinal opioid antinociceptive responses in beta-endorphin-deficient mutant mice. Neuroscience 101:709-17