BLOCKADE OF THE DEVELOPMENT OF MORPHINE-TOLERANCE BY U-50,488, AN AVPANTAGONIST OR MK-801 IN THE RAT HIPPOCAMPAL SLICE

1 In this study, we investigated the effects of different drugs (a kap pa-opioid receptor agonist U-50,488, a vasopressin receptor antagonist dPTyr(Me)AVP or an N-methyl-D-aspartate (NMDA) receptor antagonist MK -801) on the development of morphine tolerance in rat hippocampal slic es. 2 Hippocampal slices (450 mu m) of Sprague-Dawley rats (250-300 g) were used. Slices were continuously superfused with artificial CSF or drugs at 1 ml min(-1). Nichrome wire electrodes were placed in the Sc haffer-collateral pathway and used to deliver biphasic 0.2 ms pulses o f 5-30 V (0.033 Hz). A glass microelectrode was placed in the CA1 area to record population spikes. 3 When the slices were superfused with 1 0 mu M morphine, the amplitude of population spikes increased 2-3 fold in 30-40 min. However, this effect of morphine decreased, i.e; tolera nce developed after continuous superfusion of morphine for 2-6 h. 4 Wh en either U-50,488 (200 nM) or dPTyr(Me) AVP (500 pM) or MK-801 (500 p M) was co-superfused with morphine (10 mu M), it significantly blocked the development of morphine tolerance. Nor-BNI (a kappa-opioid recept or antagonist, 200 nM) significantly reversed the inhibitory effect of U-50,488 but not those of dPTyr(Me)AVP or MK-801 on the development o f morphine tolerance. 5 These data indicate that kappa-opioid receptor s, AVP receptors and NMDA receptors are all involved in the developmen t of morphine tolerance. The suppression of kappa-opioid receptor acti vity after chronic morphine may occur before the activation of AVP rec eptors or NMDA receptors during the development of morphine tolerance.