Comparison of Opiate/Opioid Receptors in the Ans and CNS

Glasel, Jay

Abstract

This is a resubmission of 1R01 NS18017-01 which was approved with good priority but not funded. The proposal has been revised and updated in the light of further preliminary work and study section suggestions. The basic objective of the research is the isolation and characterization, at the molecular level, of opiate and opioid receptors derived from subcellular fractions of CNS and ANS neural tissue. The current evidence for the existence of multiple opiate/opioid receptors in CNS and ANS tissue demands clarification and is closely allied with integrative phenomena in both nervous systems. We will first concentrate on a programmed use of radiation inactivation techniques to determine the gross molecular features of receptors in the different tissues. The step beyond this will be to raise, purify, isolate and characterize monoclonal anti-receptor antibodies. These will be used as tools for investigating receptor heterogeneity in tissue situated receptors in more detail. They will also serve as starting points for more detailed in vivo physiological work to be carried out beyond this grant period. We will also use these materials as affinity purification reagents in the isolation of receptor macromolecules. In addition, we will collaborate with at least one other laboratory on the development of new ligands for opiate/opioid receptors which would aid us in obtaining more complete and reliable characterization of their properties. In particular we have in mind possible development of ligands which may have selective interaction profiles towards Mu, Delta or Kappa receptors. Our long range goal is understanding the sequence of molecular events in neuromembranes following opiate/opioid ligand reception and their integration into the CNS (as exemplified by spino-thalamic, and spino-reticulo thalamic pain pathways) and ANS (as exemplified by the relationships between visceral-sensory and visceral-motor pathways).