Morphine-induced excitation of pyramidal neurons is inhibited by cholecystokinin in the CA1 region of the rat hippocampal slice.
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)
Miller
K K
KK
Department of Pharmacology, University of Colorado Health Sciences Center, Denver.
Lupica
C R
CR
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*
D009020:Morphine; D012844:Sincalide