EFFECT OF CCK RECEPTOR ANTAGONISTS ON THE ANTINOCICEPTIVE, REINFORCING AND GUT MOTILITY PROPERTIES OF MORPHINE

1 The ability of a selective CCKA receptor antagonist PD 140548 and a selective CCKB receptor antagonist CI-988 (formerly PD 134308) to modu late the various in vivo properties of morphine was investigated in th e rat. 2 PD 140548 dose-dependently (0.001 - 1.0 mg kg(-1), i.p.) anta gonised the development of conditioned place preference to morphine (2 .0 mg kg(-1), s.c.). In contrast, CI-988 (0.01 - 1.0 mg kg(-1), i.p.) did not affect this morphine-induced behaviour. Neither of the CCK rec eptor antagonists blocked or generalised to the morphine (3.0 mg kg(-1 ), i.p.) discriminative stimulus. 3 CI-988 (0.001 - 10.0 mg kg(-1), s. c.) at doses of 0.05 and 0.1 mg kg(-1) (s.c.), potentiated the antinoc iceptive action of a threshold dose of morphine (5.0 mg kg(-1), i.p.) in a radiant heat model of acute nociception, the rat tail flick test. Furthermore, at 0.01 mg kg(-1) it potentiated the antinociceptive act ion of morphine (3.0 mg kg(-1)) during the acute phase of the rat paw formalin test. And at doses of 0.01 and 0.1 mg kg(-1) it also potentia ted the antinociceptive action of morphine (1.0 mg kg(-1)) during the tonic phase of the formalin test. However, in both models, higher dose s of CI-988 were ineffective. In contrast, PD 140548 (0.001 - 10 mg kg (-1), s.c.) was only active at a dose of 1.0 mg kg(-1) (s.c.) and only in the tonic phase of the formalin test. Neither CI-988 nor PD 140548 possessed any intrinsic antinociceptive action in either of the tests . Chronic treatment with CI-988 (0.01 mg kg(-1) s.c.) prevented the de velopment of tolerance to morphine antinociception (4 mg kg(-1), s.c.) following a 6 day period of twice daily injections of morphine escala ting from 1 to 16 mg kg(-1) (i.p.). 4 Morphine dose-dependently (1 - 1 0 mg kg(-1), s.c.) reduced the distance travelled by a charcoal meal i n the rat intestine. Neither PD 140548 (0.01 - 1.0 mg kg(-1), i.p.) no r CI-988 (0.01 - 1.0 mg kg(-1), i.p.) potentiated or suppressed this i nhibitory action of morphine. 5 In conclusion, the results of the pres ent study indicate that CCKA and CCKB receptors modulate different pro perties of morphine. Thus, whilst a selective CCKA receptor antagonist blocked the rewarding properties of morphine, a selective CCKB recept or antagonist potentiated the antinociceptive action. However, neither compound displayed a potential for modulating the in influence of mor phine on gastro-intestinal motility. It is suggested that these findin gs may have important implications for development of CCK receptor ant agonists as analgesic adjuncts to the therapeutic use of morphine.