delta(2)-Opioid receptor mediation of morphine-induced CCK release in the frontal cortex of the freely moving rat

Numerous pharmacological data have been accumulated in support of the exist ence of physiological interactions between cholecystokinin (CCK) and opioid s in the central nervous system. With the aim of further characterizing the se interactions, an in vivo microdialysis approach was used to directly ass ess the possible influence of opioids on the extracellular levels of CCK-li ke material (CCKLM) in the frontal cortex of the awake, freely moving rat. Systemic administration of a high dose of morphine (10 mg/kg i.p.) produced a marked increase (up to +200%) of cortical CCKLM outflow, and this effect could be completely prevented by systemic (1.5 mg/kg i.p.) as well as intr acortical (10 mu M) administration of the opioid receptor antagonist naloxo ne. The opioid receptors activated by morphine appeared to be of the delta type because the intracortical infusion of naltrindole (10 mu M) also preve nted the effect of morphine, whereas CTOP (10 mu M), a selective mu-opioid receptor antagonist, and nor-binaltorphimine (10 mu M), a selective kappa-o pioid receptor antagonist, were inactive. In addition, naltriben (10 mu M), which acts selectively at the delta(2) subtype, also abolished the stimula tory effect of morphine on cortical CCKLM outflow, whereas 7-benzylidenenal trexone (10 mu M), a selective delta(1)-opioid receptor antagonist (10 mu M ), did not alter the morphine effect. Conversely, the direct stimulation of cortical Ga-opioid receptors by local infusion of [D-Ala(2)] deltorphin II mimicked the stimulatory effect of systemic morphine on CCKLM outflow. The se data indicate that delta(2)-opioid receptors play a key role in opioid-C CK interactions in the rat frontal cortex. (C) 1999 Wiley-Liss, Inc.