Morphine produces analgesia at opiate receptors expressed in nociceptive circuits. , ␦, and opiate receptor subtypes are expressed in circuits that can modulate nociception and receive inputs from endogenous opioid neuropeptide ligands. The roles played by each receptor subtype in nociceptive processing in drug-free and morphine-treated states have not been clear, however. We produced homologous, recombinant , opiate receptor, heterozygous and homozygous knockout animals that displayed Ϸ54% and 0% of wild-type levels of receptor expression, respectively. These mice expressed receptors and ␦ receptors at near wild-type levels. Untreated knockout mice displayed shorter latencies on tail f lick and hot plate tests for spinal and supraspinal nociceptive responses than wild-type mice. These findings support a significant role for endogenous opioid-peptide interactions with opiate receptors in normal nociceptive processing. Morphine failed to significantly reduce nociceptive responses in hot plate or tail f lick tests of homozygous receptor knockout mice, and heterozygote mice displayed right and downward shifts in morphine analgesia dose-effect relationships. These results implicate endogenous opioidpeptide actions at opiate receptors in several tests of nociceptive responsiveness and support receptor mediation of morphine-induced analgesia in tests of spinal and supraspinal analgesia.Morphine acts at seven transmembrane domain, G proteinlinked receptor products of genes encoding , , and ␦ opiate receptor subtypes (1-9). Each of these genes is expressed in neurons in several neuronal circuits implicated in nociception (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20).receptor mediation of much morphine-induced analgesia has been postulated (21, 22). However, studies using compounds with relative preferences for ␦ and receptors have suggested that these other two opiate receptor subtypes also might play significant roles in the analgesic responses induced by morphine-like drugs (22-26). The extent to which each of the three opiate receptor subtype gene products might participate in different features of opiate-or morphineinduced analgesia thus has remained unclear. Elucidation of the selective analgesic contributions of each opiate receptor subtype is of substantial potential importance for developing improved analgesic medications with minimal undesirable effects.Expression of endogenous opioid-peptide agonists, especially those derived from the preproenkephalin and preprodynorphin genes, in circuits associated with pain perception suggests that opioid-peptide interactions with opiate receptors could be well positioned to modulate nociceptive responses in the absence of exogenously administered opiate drugs (10,12,14,(27)(28)(29)(30)(31)(32). Studies of pain responses in animals and humans treated with opiate antagonists, however, have documented modifications in nociception in some but not all studies (33,34). These results also have left uncertainty about the power of endogenous opioid-peptide interactions with ...

Homozygous transgenic knockout mice without -opioid receptors lack morphine-induced antinociception