Opioids..decoupling pain from itching...here we go

Animal researchers are making remarkable progress in understanding the complex neurophysiologic interrelationships between the sensations of itch and pain. Recent discoveries in this area have the potential to transform the clinical management of human pain, especially for patients who experience intense itching in association with the in-hospital administration of epidural morphine. Among the most promising of these discoveries, in late 2011, using a mouse model, a group from the Washington University School of Medicine was successful in uncoupling the desired analgesic effect of morphine from the unwanted effect of itching.¹

The strategy employed by the researchers was a sequential series of molecular, cellular, biochemical, and behavioral experiments that culminated in blocking one variant of the μ-opioid receptor, MOR1D.¹ The group’s strategy built on earlier findings that showed MOR1 is the predominant receptor mediating the analgesic effects of morphine in the spinal cord, and that one particular isoform, MOR1D (differing from MOR1 by only 7 amino acids), induces itching by activating gastrin-releasing peptide receptor (GRPR).¹ GRPR is co-expressed with MOR1D in spinal cord neurons and importantly, transmits the sensation of itch but not pain.^1,2 Prior to the discovery that GRPR-expressing neurons represent a “labeled line” for the transmission of itch signals in the spinal cord, suppression of pain signaling was thought to be necessary for the perception of itch (a concept termed the “selectivity” theory).^1,3 The finding of an opioid receptor variant, MOR1D, that does not alleviate pain, together with the discovery of an itch-specific receptor, GRPR, represents a noteworthy scientific breakthrough. Similar investigative approaches are now being applied to decoupling analgesia from the other dose-limiting side effects of opioids, namely nausea, constipation, and respiratory depression.^4,5 In addition, novel therapies for debilitating itching may also develop out of this important research aimed at improving the tolerability of opioids.²

1. Liu X, Liu Z, Sun Y, et al. Unidirectional Cross-Activation of GRPR by MOR1D Uncouples Itch and Analgesia Induced by Opioids. Cell 2011 October 14;147(2):447-458.  [PMID: 22000021]

2. Cevikbas F, Steinhoff M, Ikoma A. Role of spinal neurotransmitter receptors in itch: new insights into therapies and drug development. CNS Neurosci Ther 2011 December;17(6):742-749.  [PMID: 20950328]

3. Miyamoto T, Patapoutian A. Why Does Morphine Make You Itch? [editorial]. Cell 2011 October 14;147(2):261-262.  [PMID: 22000005]

4. Dryden J. Researchers block morphine’s itchy side effect. October 13, 2011. Newsroom. Washington University in St. Louis. Copyright 2010.https://news.wustl.edu/news/Pages/22805.aspx.

5. Ross SE. Pain and itch: insights into the neural circuits of aversive somatosensation in health and disease. Current Opinion in Neurobiology 2011 December;21(6):880-887.  [PMID: 22054924]