To search for novel compounds with selective agonist activity at d-opioid receptors by screening cDNA libraries from skin of several frog species
To develop mice deficient in d-opioid receptors using the 'knockout technique' and by treatment with antisense oligonucleotides directed to the d-opioid receptor
To assess the role of d-opioid receptors in pain and drug addiction by behavioural, neuroanatomical and biochemical studies in normal and d-opioid receptor deficient animals
The cloning of the d-opioid receptor and the discovery of selective compounds which act at this site has provided the opportunity to study the role of this receptor in the regulation of brain function and to assess the potential therapeutic importance of new compounds acting at this receptor in the treatment of pain and in drug addiction. The primary objective of the proposed project is to determine the role of d-receptors in pain and in motivational and rewarding aspects of opioids which may be responsible for drug addiction. The work programme will involve the development of novel compounds which act at the d-receptor by screening of cDNA libraries from frog skin, an approach which has previously been successful in obtaining highly selective tools active at the d-receptor. Using these and other d-agonists and antagonists, which have recently become available, behavioural studies, brain imaging of receptor proteins and mRNA encoding for the d-receptor, plus microdialysis techniques will be used to study d-receptor mediated changes in neurotransmitter release. To further probe the role of d-receptors, mutant 'knockout mice', deficient in d-opioid receptors, will be developed and treatments with antisense oligonucleotides directed to the d-receptor plus chronic antagonist treatment during development will be used to address the changes that occur in pain and in addictive processes in animals whose d-receptors have been disabled. These multidisciplinary approaches will allow evaluation of the physiological role of d-receptors in specific brain functions and will enable a clear delineation of a potential clinical utilisation of d-receptor active drugs. Throughout the work programme, using the novel tools outlined above, the issue of whether subtypes of the d-receptor exist and make a distinct contribution to pain suppression and addictive mechanisms will be addressed. The project will enhance our understanding of the role of d-receptors in pain and provide, by the discovery of novel d-opioid receptor peptides, potential new therapies for pain. It will also increase our understanding of the biological effects of illicit drugs on the structure and function of the brain by identifying the role of d-opioid receptors in dependence producing mechanisms. The project will also be using state of the art imaging techniques to map receptors and their genetic message in structures in the brain.
Funding SchemeCSC - Cost-sharing contracts