The long term goals of this research project are to find novel ligands with novel biological profiles that will mediate prolonged pain including neuropathic pain without the toxic side effects of current opioids used in clinical medicine. Recent physiological, pharmacological, and biochemical studies provides evidence that in persistent pain states the expression and activity of neuropeptides and their receptors are different than in normal physiological states. In this multidisciplinary proposal involving three different laboratories, we will exploit recent developments in de novo design, pain-related pharmacology, physiology and molecular biology to develop new classes ligands that will test the hypotheses that ligands with a profile of opioid receptor agonist activities and neurokinin I antagonist activities will show outstanding antinociceptive and antiallodynic efficacy in prolonged pain states and will not demonstrate tolerance. Our Specific Aims are:1) To design, synthesize and evaluate in vitro novel peptidomimetics, non-peptides conjugates that opioid receptor agonist activities AND NK1 receptor selective antagonist activities; 2) To develop synthetic methods to make Specific Aim 1 possible; 3) To utilize biophysical methods (NMR, X-ray, PWR spectroscopy, etc.) in conjunction with computational chemistry to determine the 3-D pharmacophores for further design; 4) To examine the ligands for their binding affinities and GTPgammaS binding using rat brain homegenates and stably transfected cell lines containing human opioid receptors, and examine binding to NK1 receptor and their antagonist properties using PI hydrolysis assays; 5) To demonstrate the in vivo biological activity of these compounds in several pain models and the neuroadaptive changes; 6) To demonstrate lack of tolerance with repeated administration of our novel ligands; 7) To continue to search for novel ligands that are highly selective systemically active mu receptor antagonists novel ligands with novel biological activity profiles and novel mechanisms of action for pain control will result from these studies.