Molecular pharmacology of opioid receptors

Abstract

We cloned κ and µ opioid receptor cDNAs. Using these cDNAs, first, we examined the molecular mechanism for the subtype selectivity of opioid ligands, especially a µ-selective ligand DAMGO. Binding experiments using various chimera and mutated receptors revealed that DAMGO discriminates between µ and δ receptors by recognizing the difference in only one amino acid residue, that is, N¹²⁷ in µ and K¹⁰⁸ in δ, at the first extracellular loop, and that it distinguishes between µ and κ receptors by the difference in four amino acid residues at the third extracellular loop. Second, we established the cell lines expressing the cloned µ, δ, or κ receptor and elucidated the pharmacological properties, that is, binding affinity and agonistic activity of several opioid agonists. Third, distribution of the mRNAs for µ, δ, and κ receptors in the brain, spinal cord, and DRG was examined by in situ hybridization histochemistry (ISHH). Double ISHH demonstrated that most of the substance P-producing DRG neurons express the µ receptor. Recently, we are interested in the emotional aspect of pain and its regulation by opioids. Behavioral and microdialysis studies showed that sustained pain evoked by the intraplanter injection of formalin induced conditioned place aversion through the increment of glutamate release followed by the activation of NMDA receptors in the basolateral nucleus of amygdala (BLA). Intra-BLA injection of morphine suppressed the place aversion by inhibiting the glutamate release.