Indirect involvement of delta opioid receptors in cholecystokinin octapeptide-induced analgesia in mice.
Sulfated cholecystokinin octapeptide (CCK-8; Asp-Tyr-SO3H-Met-Gly-Trp-Met-Asp-Phe-NH2) produced analgesia in mice when administered i.c.v. and tested in the acetic acid-induced writhing assay. The ED50 was found to be 0.03 nmol/mouse which was about 3, 24 and 714 times more potent than morphine. [D-Pen2,D-Pen5]enkephalin and U50,488H [trans-(+/-)-3,4-dichloro-N-methyl-N-[2-(1-pyrolidinyl)cyclohexyl] benzeneacetamidel], respectively. When administered i.t., CCK-8 produced partial analgesia of up to 22 to 23% at low doses ranging from 15 to 60 ng/mouse and hyperalgesia at doses over 120 ng/mouse. Naloxone, an opioid antagonist, inhibited the analgesia induced by CCK-8 (i.c.v. and i.t.) but potentiated hyperalgesia induced by CCK-8 (i.t.). Apparent pA2 value for CCK-8 (i.c.v.) against naloxone (s.c.) was 5.88 which was significantly different from those for morphine-naloxone and U50,488H-naloxone but was not significantly different from that for [D-Pen2,D-Pen5]enkephalin-naloxone. Studies using highly selective opioid antagonists showed that CCK-8-induced analgesia was significantly antagonized by the delta receptor antagonist, ICI154,129 [(Allyl)2-Tyr-gly-gly-psi-(CH2S)-Phe-Leu] but not by beta-funaltrexamine, a highly selective mu receptor antagonist or nor-binaltorphimine, a highly selective kappa receptor antagonist. Opioid receptor binding study using [3H]-[D-Ala2,D-Leu5]enkephalin (+unlabeled [D-Ala2,MePhe4,Gly-ol5]enkephalin) in mouse brain membrane preparations revealed that there were no changes in the maximum binding or Kd of delta opioid binding sites in the presence of CCK-8 (1 microM) in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)
Hong
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EK
Department of Pharmacology, Medical School, University of Minnesota, Minneapolis.
Takemori
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AE
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D000698:Analgesia; D000818:Animals; D004723:Endorphins / Q000378:metabolism; D020881:Enkephalin, D-Penicillamine (2,5)-; D004745:Enkephalins / Q000494:pharmacology; D008297:Male; D051379:Mice; D009270:Naloxone / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D011957:Receptors, Opioid / Q000502:physiology; D017465:Receptors, Opioid, delta; D012844:Sincalide / Q000378:metabolism / Q000494:pharmacology*
D004723:Endorphins; D004745:Enkephalins; D011759:Pyrrolidines; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D009270:Naloxone; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D020881:Enkephalin, D-Penicillamine (2,5)-; D012844:Sincalide