Nociceptin activation of ORL1 (opioid receptor-like 1 receptor) has been shown to antagonize μ receptor-mediated analgesia at the supraspinal level. ORL1 and μ-opioid receptor (μR) are co-expressed in several subpopulations of CNS neurons involved in regulating pain transmission. The amino acid sequence of ORL1 also shares a high degree of homology with that of μ receptor. Thus, it is hypothesized that ORL1 and μR interact to form the heterodimer and that ORL1/μR heterodimerization may be one molecular basis for ORL1-mediated antiopioid effects in the brain. To test this hypothesis, myc-tagged ORL1 and HA-tagged μR are co-expressed in human embryonic kidney (HEK) 293 cells. Co-immunoprecipitation experiments demonstrate that ORL1 dimerizes with μR and that intracellular C-terminal tails of ORL1 and μR are required for the formation of ORL1/μR heterodimer. Second messenger assays further indicate that formation of ORL1/μR heterodimer selectively induces cross-desensitization of μR and impairs the potency by which [D-Ala2,N-methyl-Phe4,Glyol5]enkephalin (DAMGO) inhibits adenylate cyclase and stimulates p42/p44 mitogen-activated protein kinase (MAPK) phosphorylation. These results provide the evidence that ORL1/μR heterodimerization and the resulting impairment of μ receptor-activated signaling pathways may contribute to ORL1-mediated antiopioid effects in the brain.
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