THE ROLE OF GLUTAMATE IN THE LOCUS-COERULEUS DURING OPIOID WITHDRAWALAND EFFECTS OF H-7, A PROTEIN-KINASE INHIBITOR, ON THE ACTION OF GLUTAMATE IN RATS

To investigate the role of glutamate in the locus coeruleus (LC) durin g opioid withdrawal, rats were continuously infused with morphine (a m u-opioid receptor agonist, 26 nmol/mu l/h) or butorphanol (a mu/delta/ kappa-mixed opioid receptor agonist, 26 nmol/mu l/h) intracerebroventr icularly (i.c.v.) via osmotic minipumps for 3 days. A direct LC inject ion of glutamate (1 or 10 nmol/5 mu l) or naloxone (an opioid receptor antagonist, 24 nmol/5 mu l) induced withdrawal signs in morphine- or butorphanol-dependent animals. However, these agents failed to precipi tate any withdrawal signs in saline-treated control animals. On the ot her hand, the expression of withdrawal signs precipitated by the admin istration of glutamate or naloxone in opioid-dependent animals was com pletely blocked by concomitant infusion with 1 or 10 nmol/mu l/h of an inhibitor of adenosine 3',5'-cyclic monophosphate (cAMP)-dependent pr otein kinase and protein kinase C, H-7 [1-(5-isoquinolinesulfonyl)-2-m ethylpiperazine]. In animals that had been infused with opioids in the same manner, i.c.v. injection of naloxone (48 nmol/5 mu l) precipitat ed withdrawal signs and increased extracellular fluid levels of glutam ate in the LC of morphine- or butorphanol-dependent rats measured by i n vivo microdialysis method. However, concomitant infusion with H-7 in hibited the increases of glutamate levels in the LC. These results str ongly suggest that an expeditious release of glutamate in the LC regio n plays an important role in the expression of physical dependence on opioids. Furthermore, the action on glutamate release might be increas ed by the enhancement of cAMP-dependent protein kinase and/or protein kinase C activity.