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Effect of CCK receptor antagonists on the antinociceptive, reinforcing and gut motility properties of morphine
Author(s) -
Singh L.,
Oles R.J.,
Field M.J.,
Atwal P.,
Woodruff G.N.,
Hunter J.C.
Publication year - 1996
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1996.tb15539.x
Subject(s) - morphine , nociception , pharmacology , antagonist , chemistry , receptor antagonist , conditioned place preference , receptor , tail flick test , medicine , biochemistry
1 The ability of a selective CCK A receptor antagonist PD 140548 and a selective CCK B receptor antagonist CI‐988 (formerly PD 134308) to modulate the various in vivo properties of morphine was investigated in the rat. 2 PD 140548 dose‐dependently (0.001‐1.0 mg kg −1 , i.p.) antagonised 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 receptor 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 antinociceptive 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 action 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 potentiated the antinociceptive action of morphine (1.0 mg kg −1 ) during the tonic phase of the formalin test. However, in both models, higher doses 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 development of tolerance to morphine antinociception (4 mg kg −1 , s.c.) following a 6 day period of twice daily injections of morphine escalating from 1 to 16 mg kg −1 (i.p.). 4 Morphine dose‐dependently (1–10 mg kg −1 , s.c.) reduced the distance travelled by a charcoal meal in the rat intestine. Neither PD 140548 (0.01‐1.0 mg kg −1 , i.p.) nor CI‐988 (0.01‐1.0 mg kg −1 , i.p.) potentiated or suppressed this inhibitory action of morphine. 5 In conclusion, the results of the present study indicate that CCK A and CCK B receptors modulate different properties of morphine. Thus, whilst a selective CCK A receptor antagonist blocked the rewarding properties of morphine, a selective CCK B receptor antagonist potentiated the antinociceptive action. However, neither compound displayed a potential for modulating the influence of morphine on gastro‐intestinal motility. It is suggested that these findings may have important implications for development of CCK receptor antagonists as analgesic adjuncts to the therapeutic use of morphine.