The endogenous opioid peptides appear to play an important role in modulating the bi-directional motivational effects of opioids. These motivational effects of opioids are mediated by the mesolimbic dopamine neurons ascending from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) and medial frontal cortex (MFC). Depending on the opioid receptors stimulated, either rewarding or aversive effects of opioids can be demonstrated. The activation of u or &-opioid receptors increases the release of dopamine in the NAc or MFC and produces place preference, while activation of K-OpiOid receptors decreases the release of dopainine and produces place aversion. The fmding that opioid antagonist naloxone produces place aversion indicates that the endogenous opioid systems are tonically active in modulating the place conditioning behaviors. The likely endogenous ligands for the reward are b-endorphins, Met-enkephalin and endomorphins, and the endogenous ligand for the aversion is likely to be dynorphin(1-17). Present research is to study the neuronal mechanisms of motivational effects, e.g.place conditioning, of b-endorphin, endomorphin-1, endomorphin-2 Met-enkephalin and dynorphin(1-17). Experiments will be mainly performed in rats. Microinjection technique will be used to determine the brain sites Sensitive to these opioids on the production of place preference or aversion. We propose that opioids produce their pharmacological actions in part by releasing endogenous opioid peptides following an initial stimulation of the opioid receptors. Pharmacologically the effects of pretreatment with antibodies against opioid peptides on opioid-induced place conditioning, and biochemically the release of endogenous opioid peptides induced by stimulation of applied opioids will be studied. The modulation of dopamine release by opioids will also be studied. Intraventricualr perfusion technique and microdialysis probes will be used to measure the release of opioid peptides into the ventricualr space and the releases of opioid peptides and dopamine from circumscribed regions of the brain. Opioid peptides will be measured by ELISA and dopamine by HLPC coupled with ECD. Antisense ODN to the opioid receptor mRNAs, which inhibit the synthesis of receptor proteins, will be used to identify the types of the receptors, which might be involved in the opioid-induced place preference/aversion. In addition, uL-opioid receptor and preproenkepahlin knockout mice will be used to determine if the u-opioid receptors, Met-enkephalin are involved in place conditioning induced by endogenous opioids. The overall goal of the present research is to determine the role of endogenous opioid peptides in place conditioning. Attempt will be made to seek if there are correlative relationships among brain sites sensitive to opioids for the production of place preference or place aversion and the releases of opioid peptides and dopatnine.
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