The analgesic properties of the opioids are primarily mediated by the µ receptors. However, the κ receptors in the dorsal horn also contribute (eg, butorphanol and nalbuphine) primarily owe their analgesic effect to κ-receptor activation. The enkephalins interact more selectively with the δ receptors in the periphery. All three opioid receptors are members of the G protein–coupled receptor family and inhibit adenylyl cyclase. They are also associated with ion channels, increasing postsynaptic K+ efflux hyperpolarization or reducing presynaptic Ca2+ influx, thus impeding neuronal firing and transmitter release . opioid receptors are located on primary afferents and spinal cord pain transmission neurons (ascending pathways) and on neurons in the midbrain and medulla (descending pathways) that function in pain modulation. Other opioid receptors that may be involved in altering reactivity to pain are located on neurons in the basal ganglia, the hypothalamus, the limbic structures, and the cerebral cortex.