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 [3H]-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 wild-type (+/+) 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