Abstract

Opioids increase the excitability of CA1 pyramidal neurons in the hippocampus through the inhibition of gamma-aminobutyric acid release from interneurons. This can be observed extracellularly as an increase in population spike amplitude. The sulfated form of the neuropeptide cholecystokinin (CCK-8S) has been shown in a variety of in vivo models to inhibit the response to opioids. We have utilized the well-characterized hippocampal response to opioids to examine the potential interactions between morphine and the neuropeptide cholecystokinin (CCK) in vitro. Morphine (1-500 microM; EC50 = 22.1 microM, 95% confidence interval = 6.5-75.9 microM) alone caused concentration-dependent increases in CA1 population spike amplitudes that were reversible upon washout or application of the opioid antagonist naloxone (10 microM). In contrast to the morphine effect, CCK-8S (0.001-1 microM) had no effect alone on population spikes (99.1 +/- 1.6% of control, P > .05). However, when hippocampal slices were pretreated with CCK-8S (0.1-1 microM), the morphine-induced increase in population spike amplitudes was blocked in a noncompetitive, reversible manner (IC50 = 17.8 nM, 95% confidence interval = 9.5-33.7 nM). This antagonism of morphine action by CCK-8S was not seen when CCK-8S was added after the opiate had achieved its maximal effect, and was blocked completely by the application of the selective CCKB receptor antagonist PD-135, 158 (1.5 microM). The unsulfated form of CCK, unlike CCK-8S, did not antagonize the excitatory actions of morphine on population spikes.(ABSTRACT TRUNCATED AT 250 WORDS)