Itching is one of the most prevalent side effects of powerful, pain-killing drugs like morphine, oxycodone and other opioids. The opiate-associated itch is so common that even women who get epidurals for labor pain often complain of itching. For many years, scientists have scratched their own heads about why drugs that so effectively suppress pain also induce itch.
Now in mice, researchers at Washington University School of Medicine in St. Louis have shown they can control opioid-induced itching without interfering with a drug's ability to relieve pain. The discovery raises tantalizing possibilities for new treatments to eliminate itch in cancer and surgery patients as well as others who rely on opioids to relieve chronic and severe pain.
The investigators report the findings Oct. 14 in the journal Cell.
By identifying and blocking a specific variant of the opioid receptor in the spinal cord, Zhou-Feng Chen, PhD, director of Washington University's Center for the Study of Itch, a newly established multidisciplinary center aimed at translating basic itch research into novel treatments, and his colleagues have demonstrated for the first time that it is possible to inhibit itch without dulling morphine's pain-killing effects.
"We've known for decades that there are a number of variants of the opioid receptor, but unfortunately, their physiological importance has been largely overlooked," says Chen, principal investigator on the study. "We identified a particular variant of the receptor called MOR1D that mediates itch. When we blocked MOR1D, mice that got morphine no longer needed to scratch, and they still received the same level of pain relief."
In previous studies, Chen, a professor of anesthesiology, of psychiatry and of developmental biology, had identified an itch-specific receptor in the spinal cord called GRPR (gastrin-releasing peptide receptor). His studies also have shown that neurons containing GRPR specifically transmit itch but do not carry pain information. In the new study, his team found that the opioid receptor MOR1D induced itching in the mice on morphine by activating GRPR.
"It is exciting to know that MORID actually functions as an itch-specific receptor," Chen says. "Depending on different types of itch-producing substances, our study suggests that the body has different ways of activating GRPR to transmit itch. In this case, opioids such as morphine first activate MOR1D, and that receptor subsequently connects to GRPR to relay itch signals."
In a surprising twist, first author Xian-Yu Liu, PhD, a postdoctoral researcher in Chen's lab, found that a major variant of the opioid receptor called MOR1 exclusively mediates morphine's analgesic effects in the spinal cord. When he blocked MOR1D, the mice no longer scratched. When he blocked MOR1, the animals no longer received the drug's pain-killing benefits, but they continued to scratch.
"Scientists have blamed the wrong receptor, but now the culprit has been caught," Chen says. "There are more than a dozen forms of the opioid receptor on nerve cells, but MOR1D is the first one that has nothing to do with killing pain. It only transmits itch."
Other side effects of opioids also have been extremely difficult to separate from the drugs' analgesic effects. But the current study makes Chen suspect that other variants of the receptor may be related to nausea, respiratory depression, constipation or other common side effects associated with the use of pain-killing drugs.
Chen hopes his research will motivate other investigators to look more closely at whether other opioid receptor variants may be responsible for these additional side effects.
"They may do all sorts of different things under the same 'disguise,'" Chen says. "If so, the implications could be clinically significant."
Chen says at first glance, MOR1 and MOR1D appear almost identical, the "bad guy" dressed in the "good guy's" clothing. The only difference is that MOR1 does not have seven amino acids found in MOR1D. But he says those seven amino acids turn out to be critical for the interaction between MOR1D and GRPR in the spinal cord.
"They operate like a key that can be used to open a door," he says. "Without the key, MOR1 can't activate GRPR even though the receptor is activated by morphine."
He says the finding opens up new possibilities for designing novel therapeutic strategies to relieve opioid-induced itching without blocking the analgesic effects of the drugs.
"If you can somewhow alter the key, you may eliminate itching without actually destroying MOR1D and GRPR," Chen says. "We wouldn't want to knock out those receptors in people because it's possible that they may have other important functions not related to itching."
Chen's team plans to look more closely at other opioid receptors to learn what they do, but he also hopes to quickly determine whether blocking MOR1D might alleviate itch people taking morphine or other opioids.
"There is a similar MOR1D receptor in humans, so we hope to find out whether blocking the same receptor in patients could alleviate itching without interfering with the analgesic effects of pain-killing drugs," he says.
- Liu XY, Liu ZC, Sun YG, Ross M, Kim S, Tsai FF, Li QF, Jeffry J, Kim JY, Loh HH, Chen ZF. Unidirectional cross-activation of GRPR by MOR1D uncouples itch and analgesia induced by opioids. Cell, vol. 147. Oct. 14, 2011 DOI: 10.1016/j.cell.2011.08.043
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