Research ArticleITCH

Morphine acts on spinal dynorphin neurons to cause itch through disinhibition

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Science Translational Medicine  03 Feb 2021:
Vol. 13, Issue 579, eabc3774
DOI: 10.1126/scitranslmed.abc3774

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The pain and the itch

Spinal and epidural morphine administration is used in the clinic as analgesic for a number of surgical procedures and in women during labor. However, delivery through these routes is associated with the development of itch. The molecular basis of this unwanted side effect is unclear. Now, Nguyen et al. showed that morphine-induced itch did not involve mast cells but was mediated by the activity of spinal dynorphin neurons and subsequent inhibition of kappa-opioid receptor-expressing neurons in mice. Concomitant administration of morphine and nalfurafine, a selective kappa-opioid receptor agonist, inhibited itch without affecting morphine’s analgesic properties in mice and monkeys, suggesting that this approach might be effective also in the clinic.

Abstract

Morphine-induced itch is a very common and debilitating side effect that occurs in laboring women who receive epidural analgesia and in patients who receive spinal morphine for relief of perioperative pain. Although antihistamines are still widely prescribed for the treatment of morphine-induced itch, their use is controversial because the cellular basis for morphine-induced itch remains unclear. Here, we used animal models and show that neuraxial morphine causes itch through neurons and not mast cells. In particular, we found that spinal dynorphin (Pdyn) neurons are both necessary and sufficient for morphine-induced itch in mice. Agonism of the kappa-opioid receptor alleviated morphine-induced itch in mice and nonhuman primates. Thus, our findings not only reveal that morphine causes itch through a mechanism of disinhibition but also challenge the long-standing use of antihistamines, thereby informing the treatment of millions worldwide.

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