Generation of a MOR-CreER knock-in mouse line to study cells and neural circuits involved in mu opioid receptor signaling.

Mu opioid receptor (MOR) is involved in various brain functions, such as pain modulation, reward processing, and addictive behaviors, and mediates the main pharmacologic effects of morphine and other opioid compounds. To gain genetic access to MOR-expressing cells, and to study physiological and pathological roles of MOR signaling, we generated a MOR-CreER knock-in mouse line, in which the stop codon of the Oprm1 gene was replaced by a DNA fragment encoding a T2A peptide and tamoxifen (Tm)-inducible Cre recombinase. We show that the MOR-CreER allele undergoes Tm-dependent recombination in a discrete subtype of neurons that express MOR in the adult nervous system, including the olfactory bulb, cerebral cortex, striosome compartments in the striatum, hippocampus, amygdala, thalamus, hypothalamus, interpeduncular nucleus, superior and inferior colliculi, periaqueductal gray, parabrachial nuclei, cochlear nucleus, raphe nuclei, pontine and medullary reticular formation, ambiguus nucleus, solitary nucleus, spinal cord, and dorsal root ganglia. The MOR-CreER mouse line combined with a Cre-dependent adeno-associated virus vector enables robust gene manipulation in the MOR-enriched striosomes. Furthermore, Tm treatment during prenatal development effectively induces Cre-mediated recombination. Thus, the MOR-CreER mouse is a powerful tool to study MOR-expressing cells with conditional gene manipulation in developing and mature neural tissues.