Opioid receptors are expressed by central and peripheral neurons and by neuroendocrine (pituitary, adrenal), immune, and ectodermal cells. Early binding studies and bioassays defined three main types of opioid receptors in the central nervous system, the mu, delta, and kappa receptors. Additional receptor types were proposed (e.g., sigma, epsilon, orphanin) but are no longer considered “classical” opioid receptors. The identification and sequence analysis of complementary DNA (cDNA) and the selective deletion of opioid receptor genes in mice confirmed the existence of only three genes. Opioid receptors belong to the class A gamma subgroup of seven transmembrane G protein–coupled receptors (GPCRs) and show 50–70% homology between their genes. 
Additional pharmacologic subtypes may result from alternative splicing, posttranslational modifications, and/or receptor oligomerization. Opioid receptor activation leads to opening of G protein–coupled inwardly rectifying K+ (GIRK) channels, thereby preventing neuronal excitation and/or propagation of action potentials. Opioids also inhibit Na+ channels, Ih channels, transient receptor potential vanilloid-1 (TRPV1) channels, and acid-sensing ion channels (ASICs) in DRG neurons, as well as excitatory postsynaptic currents evoked by glutamate receptors in the spinal cord. Various kinases can phosphorylate intracellular regions of opioid receptors, and GPCR kinases promote binding of arrestin molecules. The formation of arrestin–opioid receptor complexes leads to opioid receptor desensitization by preventing G protein coupling and promotes receptor internalization via clathrin-dependent pathways. Recycling of dephosphorylated opioid receptors and their reintegration into the plasma membrane reinstates signal transduction, whereas targeting to lysosomes leads to receptor degradation. Opioid peptide-containing circulating leukocytes extravasate upon activation of adhesion molecules and chemotaxis by chemokines. 
Subsequently, these leukocytes are stimulated by stress or releasing agents to secrete opioid peptides. For example, corticotropin-releasing factor (CRF), interleukin-1β (IL-1), and noradrenaline (NA, released from postganglionic sympathetic neurons) can elicit opioid release by activating their respective CRF receptors (CRFR), IL-1 receptors (IL-1R), and adrenergic receptors (AR) on leukocytes. Exogenous opioids (EOs) or endogenous opioid peptides (OPs, green triangles) bind to opioid receptors (ORs) that are synthesized in dorsal root ganglia and transported along intraaxonal microtubules to peripheral (and central) terminals of sensory neurons.

References

1.Stein C. Annu Rev Med. 2016;67:433–451.