Morphine and other opioid drugs produce analgesia in humans and antinociception in animals by direct interaction with opioid receptor proteins located on neurons in the brain and spinal cord. Knowledge of the detailed relationship between the molecular structure of the opioid drug and the molecular conformation of the opioid receptor is essential to understand pharmacological action of opioids. Whereas mammalian CNS expresses three distinct opioid receptor genes (MOR1, DOR1, KOR1), each capable of mediating antinociception in mammals, amphibians appear to mediate the antinociception effects of mu, delta, and kappa-selective opioid agonists via a single opioid receptor, termed the 'unireceptor'. The Northern grass frog, Rana pipiens, will be used for all studies and the acetic acid test used for measuring opioid antinociception. For the first time, a systematic study of opioid receptor selectivity for producing antinociception will be made by in vitro and in vivo pharmacological techniques using novel methods in an amphibian model.
The specific aims are: 1) Determine the pharmacological selectivity of spinal opioid antinociception using highly-selective opioid antagonists and selective opioid agonists, and 2) Characterize the opioid binding sites in amphibian CNS tissue homogenates using radiolabeled highly-selective opioid antagonists and selective opioid agonists. Preliminary data are presented for each of these specific aims. The proposed results will elaborate our understanding of the molecular mechanisms of opioid drugs at opioid receptors with regard to opioid antinociception in animals and analgesia in humans. Additionally as our lab is the sole purveyor of opioid pharmacology using an earlier-evolved vertebrate model, the proposed studies are a unique examination of the functional evolution of opioid receptors. These studies challenge existing paradigms and further develop a new methodology for the study of opioids. Data obtained will be significant contributions to current understanding of the functional evolution of opioid receptors with regard to opioid ligand selectivity and mediation of antinociception. This knowledge will likely contribute to the understanding of the mechanisms of opioid receptor activation and may help guide the rational development of improved therapies where opioid drugs are used or abused.
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