Recent discoveries have led to new insights into mechanisms of opioid tolerance and of abnormal pain elicited by peripheral nerve injury (neuropathic pain). One of the many common features shared by these states is enhanced expression and activity of neuropeptides at both spinal and supraspinal sites, indicative of central nervous system plasticity in pathological states. Particularly significant is the new insight that the """"""""tolerant"""""""" state is accompanied my abnormal and paradoxical opioid-induced pain. To date, attempts to treat chronic pain or to prevent the development or consequences of opioid tolerance have been based largely on our understanding of the nervous system in the physiological state. Not surprisingly, opioids do not relieve pain well in either neuropathic pain states or in the """"""""tolerant"""""""" state. This deficit in opioid efficacy is due to markedly altered characteristics of the nervous system in the pathological state. Thus, the nervous system which is the target of our treatment attempts is not the same as that for which our treatment strategies have been developed. One prominent neuropeptide that shows enhanced expression in these abnormal pain states is cholecystokinin (CCK). Indeed, CCK antagonists have been shown to prevent tolerance development and even reverse pre-established tolerance to opioid therapy. A single small molecule that is systemically available and has the profile of being a selective opioid agonist / CCK antagonist, would have very significant advantages over opioid agonists alone. This proposal seeks to identify such potential medicines and progress them through pre-clinical development. Significance: The identification of drug candidates which are CCK antagonists and opioid agonists should have tremendous activity in neuropathic pain states and in states of opioid-induced paradoxical pain (i.e., opioid tolerance). These small and drug-like molecules will have a clear and distinct advantage over existing pain-relieving therapies.