l-365260 and naltrindole

CCK has been shown to inhibit morphine antinociception, while antagonists of CCK receptors enhance morphine antinociceptive potency. These observations have led to the suggestion that CCK may function as an endogenous anti-opioid. Here, the involvement of the CCKB receptor in modulating the antinociceptive effects of morphine has been investigated by examination of the effects of a CCKB antagonist in the absence or presence of naltrindole, an opioid delta receptor antagonist. Intrathecal (i.th.) or subcutaneous (s.c.) L365,260 (a CCKB antagonist) did not produce any antinociceptive actions alone in either the rat tail-flick or hot-plate tests. L365,260 pretreatment enhanced the morphine antinociceptive response after either i.th. or s.c. administration. Naltrindole did not produce any antinociceptive effect alone and did not antagonize the antinociceptive actions of morphine after either i.th. or s.c. administration. However, naltrindole blocked the enhancement of morphine antinociception produced by L365,260 when evaluated by either route. These data suggest a tonic inhibition of enkephalin release by CCK via CCKB receptors. The subsequent enhancement of morphine antinociceptive potency may reflect the well-known modulation of morphine by enkephalins acting at opioid delta receptors.

Topics: Animals; Benzodiazepinones; Injections, Spinal; Injections, Subcutaneous; Male; Morphine; Naltrexone; Narcotic Antagonists; Nociceptors; Pain Measurement; Phenylurea Compounds; Rats; Rats, Sprague-Dawley; Receptors, Cholecystokinin; Receptors, Opioid, delta

1. The effects of selective CCKB agonists, BC 264 and BC 197 were investigated in the conditioned suppression of motility test in mice, an animal model used to select antidepressant drugs. The results showed that both CCKB agonists at doses of 3 and 30 micrograms kg-1, accentuated the suppression of motility in shocked mice and did not modify the behaviour of non-shocked mice. The effects of BC 264 were suppressed by L-365,260. 2. L-365,260 alone, at doses of 0.2 and 2 mg kg-1 decreased motor inhibition in shocked mice and had no effect in non-shocked mice. 3. The effects of L-365,260 observed in shocked mice were suppressed by naltrindole, a selective antagonist for delta-opioid receptors, suggesting the occurrence of physiological adverse interactions between CCK and opioid systems. 4. Together, these results suggest that CCKB antagonists could block centrally located CCKB receptors to produce antidepressant-like effects which could indirectly involve delta-opioid receptor stimulation.

Topics: Amino Acid Sequence; Animals; Antidepressive Agents; Behavior, Animal; Benzodiazepinones; Cholecystokinin; Conditioning, Classical; Drug Interactions; Male; Mice; Molecular Sequence Data; Motor Activity; Naltrexone; Peptide Fragments; Phenylurea Compounds; Receptors, Cholecystokinin

Topics: Amino Acid Sequence; Analgesics; Animals; Benzodiazepinones; Cholecystokinin; Devazepide; Gastric Emptying; Gastrointestinal Transit; Indoles; Male; Mice; Mice, Inbred ICR; Molecular Sequence Data; Morphinans; Naloxone; Naltrexone; Narcotic Antagonists; Peptide Fragments; Peptides; Phenylurea Compounds; Reaction Time; Receptors, Cholecystokinin; Sincalide