CHARACTERIZATION OF THE CLONED HUMAN MU-OPIOID RECEPTOR

Opioid drugs exert a wide spectrum of physiological and behavioral eff ects, including effects on pain perception, mood, motor control and au tonomic functions. The effects of opioids are mediated via a family of membrane-bound receptors, of which the most extensively characterized are the mu, delta and kappa receptors. We have now cloned the human h omolog of the mu opioid receptor and, in the present study, we have ex amined its pharmacological profile. The human mu receptor has high aff inities for several alkaloids of high abuse potential as well as a var iety of peptide and nonpeptide drugs characterized previously as mu-se lective, but not delta- or kappa-selective. Most importantly, the huma n mu receptor has higher affinity for morphine and methadone than does the rat mu receptor, despite the fact that these receptors are 95% id entical at the amino acid level. The labeling of the receptor by agoni st was decreased by nonhydrolyzable GTP analogs and by pertussis toxin treatment of cells expressing the human mu receptor, consistent with the coupling of the receptor to guanine nucleotide binding proteins. T he human mu receptor functionally couples to the inhibition of adenyly l cyclase in a stereospecific and naloxone-reversible manner. We have also investigated the distribution of mRNAs encoding the mu receptor i n human brain by Northern analysis, which demonstrates the existence o f multiple transcripts of 13.5, 11, 4.3 and 2.8 kb, which were highly expressed in the hypothalamus, thalamus and subthalamic nucleus, more moderately expressed in the amygdala and caudate nucleus and which dem onstrated lowest levels of expression in the hippocampus, substantia n igra and corpus callosum. The availability of the cloned human mu rece ptor will facilitate the identification of more specific and selective compounds with greater therapeutic potential and fewer undesirable si de effects.