Dorsal Spinal Modulation of Neuraxial Opioid-Induced Pruritus

Neuraxial administration of opioids is frequently used for pain management. Unfortunately, the high incidence of pruritus greatly diminishes the value of analgesics. At first, it was suggested that opioids elicited pruritus through the inhibition of pain. However, with the identification of gastrin-releasing peptide receptor (GRPR) as an itch-specific neural receptor and the discovery of distinct isoforms of MOR, it has been proposed that neuraxial morphine causes itch through the activation of excitatory spinal neurons expressing heterodimerized MOR1D/GRPR. Although initially appealing, the theory of direct activation of excitatory spinal neurons by opioids remains controversial. Through selective manipulation of distinct spinal circuits with a genetic approach, neuraxial opioids have been proven to cause itch through a mechanism of neuronal disinhibition. Neuraxial morphine inhibits a subpopulation of itch-inhibiting spinal interneurons, leading to the downstream disinhibition of GRPR excitatory neurons. These studies provide key insights into the neuronal basis for opioid-induced itch and the spinal modulation of the itch circuit. Future work that accounts for genetic polymorphisms of the opioid receptor and the function of opioid receptors in different populations of spinal neurons may further elucidate the mechanism of opioid-induced pruritus and guide the development of opioid analgesics that treat pain, without causing pruritus.