Analysis of Knockout Mice

Physiologic roles of the opioid receptors and endogenous opioid peptides have been investigated mainly by pharmacologic and physiologic methods. However, it has been difficult to analyze functional roles of these proteins. Recently, knockout mice, in which a specific gene is inactivated by molecular biologic methods, have been produced. By analysis of the knockout mice, we can learn

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In the μ-receptor knockout mice, analgesia, reward effect, and withdrawal effect of morphine are lost.^{[30] [31]} Morphine-induced respiratory depression was not observed in the μ-receptor knockout mice.^[32] Therefore, it was concluded that the μ-receptor is a mandatory component of the opioid system for morphine action. In the μ-receptor knockout mice, ketamine-induced respiratory depression and antinociception are diminished,^[33] suggesting that ketamine interacts with the μ-receptor, leading to these phenomena. Furthermore, the minimum alveolar concentration (MAC) of sevoflurane was significantly higher in the μ-receptor knockout mice than in wild-type mice, suggesting involvement of the μ-receptor in anesthetic potency of sevoflurane.^[32] The δ-receptor knockout mice display markedly reduced analgesic effect of the opioids selective for the δ-receptors at the spinal cord level.^[34] However, at the supraspinal level, analgesia can be induced by δ-receptor agonists in the δ-receptor knockout mice, suggesting the existence of a second δ-like analgesic system. Disruption of the κ-receptor abolishes analgesic, hypolocomotor, and aversive actions of the κ-receptor agonists and induces hyperreactivity in the abdominal constriction test, indicating that the κ-receptor is involved in the perception of visceral chemical pain.^[35]

In mice lacking β-endorphin, morphine induces normal analgesia, but naloxone-reversible stress-induced analgesia cannot be observed.^[36] The preproenkephalin knockout mice are more anxious than wild-type mice, and males display increased offensive aggressiveness.^[37] The mutant mice show marked differences in control in supraspinal, but not in spinal, responses to painful stimuli. Thus, functional roles of individual components of the opioid system have been elucidated by analysis of knockout mice. However, many points remain to be clarified.