• G W Pasternak.
• Laboratory of Molecular Neuropharmacology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. pasterng@mskmail.mskcc.org
• Neuroscientist. 2001 Jun 1; 7 (3): 220-31.

AbstractMorphine and most clinical opioids act through mu opioid receptors. Yet, their pharmacological profiles differ. The presence of incomplete cross-tolerance among these drugs clinically was one of the first indications that these mu opioids differed in their receptor mechanisms of action. This was followed by similar studies in preclinical models, which also found genetic differences in sensitivity toward morphine and other mu opioids. This concept of mu receptor multiplicity is now supported by antisense and gene knockout models. Although all the mu opioids are sensitive to antisense probes against the mu opioid receptor gene MOR-1, the sensitivity profiles of the drugs to the antisense probes differ based on the exon being targeted. Knockout mice also reveal striking differences. In one knockout mouse, morphine analgesia is completely lost while the potent mu drugs morphine-6beta-glucuronide and heroin both retain analgesic activity. Finally, cloning studies have identified at least seven different splice variants of the MOR-1 gene, with more likely. These studies illustrate the complexity of mu opioid pharmacology.

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