title: Morphine-induced excitation of pyramidal neurons is inhibited by cholecystokinin in the CA1 region of the rat hippocampal slice.
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)
authors.affiliation: Department of Pharmacology, University of Colorado Health Sciences Center, Denver.
authors.forename: K K
authors.initials: KK
authors.lastname: Miller
authors.forename: C R
authors.initials: CR
authors.lastname: Lupica
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D004347:Drug Interactions; D006624:Hippocampus / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D008969:Molecular Sequence Data; D009020:Morphine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012844:Sincalide / Q000494:pharmacology*
chemical_list: D009020:Morphine; D012844:Sincalide