Opioid Control of the In Vitro Release of Cholecystokinin‐Like Material from the Rat Substantia Nigra

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Abstract
Possible interactions between Met-enkephalin and cholecystokinin (CCK)-containing neurons in the rat sub-stantia nigra were investigated by looking for the effects of various opioid receptor ligands and inhibitors of enkephalin-degrading enzymes on the K+-evoked overflow of CCK-like material (CCKLM) from substantia nigra slices. The δ-opioid agonists d-Pen2,dPen5-enkephalin (50 μM) and Tyr-D-Thr-Gly-Phe-Leu-Thr (DTLET; 3 μM) enhanced, whereas the n-opioid agonists Tyr-D-Ala-Gly-MePhe-Gly-ol (DAGO; 10 μM) and MePhe3, D-Pro4-morphiceptin (PL 017; 10 μM) decreased, the K+-evoked release of CCKLM. By contrast, the δ-opioid agonist U-50488 H (5 μM) was inactive. The stimulatory effect of DTLET could be prevented by the 5 antagonist ICI-154129 (50 μM but not by the μ antagonist naloxone (1 μM). Conversely, the latter drug, but not ICI-154129, prevented the inhibitory effect of DAGO and PL 017. A significant increase in CCKLM overflow was observed upon tissue supervision with the peptidase inhibitors kelatorphan or bestatin plus thiorphan. This effect probably resulted from the stimulation of δ-opioid receptors by endogenous enkephalins protected from degradation, because it could be prevented by ICI-154129 (50 μM Furthermore, the peptidase inhibitors did not enhance CCKLM release further when S-opioid receptors were stimulated directly by DTLET (3 μM). These data indicate that opioids acting on d and n receptors may exert an opposite influence, i.e., excitatory and inhibitory, respectively, on CCK-containing neurons in the rat substantia nigra. Because CCK has anti-opioid properties, the δ-opioid control of CCKLM release might participate in the central mechanisms of opiate tolerance.