Stimulation of either cholecystokinin receptor subtype reduces while antagonists potentiate or sensitize a morphine-induced excitatory response

Cholecystokinin peptides (CCK) have been shown to antagonize many opioid-me diated effects. The present study was undertaken to determine whether perip heral injections of cholecystokinin sulphated octapeptide (CCK8), cholecyst okinin tetrapeptide (CCK4), the CCK1 (lorglumide) and the CCK2 (PD-135,158 and LY-225910) receptor antagonists can influence a classic morphine excita tory effect, i.e. the display of Straub tail reaction in mice (STR). A tota l of 570 female Balb/C mice were tested. Experiment 1 was undertaken to det ermine whether i.p. injections of CCK8 or CCK4 can influence STR. Each anim al was treated with i.p. injections of saline or CCK8 (10 and 20 nmol/kg) o r CCK4 (20 and 40 nmol/kg). After 30 min all animals received an i.p. injec tion of morphine hydrochloride (10.0 mg/kg). The highest doses of both CCK8 (35% STR) and CCK4 (40% STR) significantly reduced STR as compared to sali ne (85% STR) treated mice (Fisher test; P < 0.01). In experiment 2 each ani mal was treated with ip injections of saline or 1.0 mg/kg lorglumide or PD- 135,158 fifteen minutes before an injection of morphine at doses ranging fr om 1.0 to 50.0 mg/kg. In experiment 3 animals were treated with injections of saline, 0.1 or 10.0 mg/kg lorglumide or LY-225910 before an injection of a fixed MC dose (2.0 mg/kg). Both lorglumide and PD-135,158 induced a sign ificant shift to the left in the morphine dose-response curves as well as a significant decrease in ED50 of the STR. ED50 for lorglumide was significa ntly lower than ED50 for PD-135,158. Both doses of lorglumide and the highe st dose of LY-225910 significantly increased the percent of animals display ing STR. Experiment 4 was undertaken to determine whether repeated peripher al injections of morphine or the morphine-potentiating agents CCK1 (lorglum ide) and the CCK2 (LY-225910) receptor antagonists can induce morphine sens itization. Each animal was treated with 5 daily i.p. injections of saline ( control group), 1.5 mg/Kg morphine hydrochloride (group morphine), and 1.0 mg/Kg lorglumide (group LOR) or LY-225910 (group LY). One, two, three and f our weeks after the last treatment day, all animals were challenged with on e i.p. injection of morphine (1.5 mg/Kg). The morphine, LOR groups and grou p LY showed a significant increase in percentage of animals displaying STR. These data demonstrate that the blockade of endogenous CCK actions leads t o morphine sensitization probably through both CCK receptors. The present d ata are consistent with the antagonistic effects of CCK and opioids in the control of morphine-induced STR. In addition, these results suggest that bo th CCK receptors are involved in the modulatory effects of CCK on this morp hine effect, (C) 2001 Elsevier Science Inc. All rights reserved.