The cloning of opioid receptors has advanced the neurobiology of opioid drug abuse but it is still unclear why agonists for the mu-receptor have a high potential for addiction while agonists for the kappa-receptor are aversive. All three opioid receptor subtypes are substantially homologous and are linked to identical second messenger pathways and ionic channels. However, opioid receptors can be pharmacologically distinguished from one another and each receptor can mediate unique physiological actions. One hypothesis to explain why opioid receptors mediate different physiological actions is their unique anatomic location results in the receptors' different effects. A genetic approach will be used to express one receptor subtype in place of another to determine if one receptor subtype can substitute functionally for another in vivo. A gene """"""""knock-in"""""""" will be performed to replace the mu-receptor exons with the kappa-receptor exons in the mouse by using the double-replacement technique. These mutant mice will then be tested to determine if kappa-agonists mimic mu- agonists in experiments examining behavioral reinforcement to opiates, opiate dependence, opiate analgesia, and tolerance to opiates. These experiments will determine if a specific intracellular signalling pathway coupled to the mu-receptor leads to drug addiction or if drug addiction is related to activation of specific anatomical pathways in the mouse brain.
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