Proposed mechanisms of opioid-induced pruritus. This review summarizes mechanisms by which opioids could drive pruritus in the skin, dorsal root ganglia, and spinal cord dorsal horn. In the skin, systemic opioids can cause mast cell degranulation through activation of mas-related G protein–coupled receptor X2 (MRGPRX2) on mast cells. Neuraxial opioids are proposed to drive itch through spinal neurons containing the μ-opioid receptor in the spinal cord dorsal horn.