Altered pain sensitivity and morphine-induced anti-nociception in mice lacking CCK2 receptors

Rationale: Cholecystokinin (CCK) interacts with the endopioid system in the regulation of various physiological functions, including the control of pain sensitivity, motor activity and emotional behaviour. Objective: The aim of the present work was to study the pain sensitivity, morphine-induced antinociception and density of opioid receptors in mice lacking CCK2 receptors. Methods: Plantar analgesia and hotplate tests were used to evaluate pain sensitivity and morphine-induced antinociception. The parameters of opioid receptors were analysed by using [H-3]-diprenorphine binding. Results: In the plantar analgesia test the latency of hind paw withdrawal was significantly increased in CCK2 receptor deficient mice compared to wild-type (+/+) littermates. The treatment with saline reversed the reduced pain sensitivity in heterozygous (+/-) and homozygous (-/-) mice. The administration of morphine (1 mg/kg) induced a significantly stronger antinociceptive effect in homozygous (-/-) mice compared with wildtype (+/+) animals. In the hotplate test, only homozygous (-/-) mutant mice displayed the delayed latency of hind paw licking/shaking in comparison with wild-type (+/+) mice. The injection of saline and isolation of mice for 30 min reversed the delayed response in homozygous (-/-) mice. However, in this test, the anti-nociceptive action of morphine (5-10 mg/kg) in mutant mice did not differ from that in wild-type (+/+) littermates. By contrast, the jump latency was decreased in both homozygous (-/-) and heterozygous (+/-) mice in the hotplate test. The increased density of opioid receptors was established in the striatum of homozygous (-/-) mice. Conclusion: It is apparent that the targeted mutagenesis of the CCK2 receptor gene has different effects on the sensitivity of opioid receptors in various brain structures. This is a probable reason for the altered pain sensitivity and morphine-induced antinociception in mutant mice compared to wild-type (+/+) littermates.