Opioids suppress pain by inhibiting synaptic communication between neurons. Presynaptic Ca2+ channels are a key molecular target of opioids because they directly control Ca2+-evoked secretion from synaptic terminals. This proposal aims to describe the biochemical signaling between opioid receptors and Ca2+ channels and to compare this to those linking other receptors to Ca2+ channels in the same cell. The work will be performed on primary cultures of sensory neurons or on cloned opioid receptors that are expressed in cell lines. The central goal is to define the heterotrimeric G protein linking opioid receptors to Ca2+ channels. The G protein is in the Gomicron family yet is otherwise undefined. Within the Gomicron family, there are two different alpha subunits, four different beta subunits, and 7 different gamma subunits, leading 56 different possible Gomicron proteins. Quite different Gomicron proteins couple different hormone receptors to their cellular targets. This enormous diversity has important implications for the mechanisms of coupling between receptors and ion channels. We will use the anti-sense knockout method to delete specific subtypes of the three subunits and measure effects of these oblations on the ionic response to opioids. A further goal is to compare opioid signal transduction to the actions of GABAB, alpha-adrenergic, metabotropic glutamate, and somatostatin receptors on CA2+ channels in sensory neurons. Evidence in other cell suggests that some of these receptors use more complex signaling schemes than that which has been described for mu opioid receptors. These studies should provide a detailed understanding of opioid signaling in the cell that is perhaps the most important target for spinal analgesia.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32DA005667-01
Application #
2118082
Study Section
Drug Abuse Biomedical Research Review Committee (DABR)
Project Start
1995-08-24
Project End
Budget Start
1995-04-01
Budget End
1996-03-31
Support Year
1
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Oregon Health and Science University
Department
Type
Organized Research Units
DUNS #
009584210
City
Portland
State
OR
Country
United States
Zip Code
97239