Morphine and related opioids may be the most powerful painkillers we have, but their effectiveness comes at a heavy cost: Side effects range from addiction and sedation to constipation and itch. Because minimizing the negatives often means limiting pain relief, researchers are keen to uncover the pathways by which these drugs alternatively soothe and torment.
In a paper published in the October 14 issue of Cell, Zhou-Feng Chen at Washington University School of Medicine in St. Louis, Missouri, and colleagues report an important advance in separating the analgesic effects of spinal opioids from a common side effect—itch. First author Xian-Yu Liu and coworkers show that in mice, spinal morphine induces itch through a dedicated μ-opioid receptor 1 splice variant, MOR1D, that is not required for the pain-killing effects of the drug. The researchers also show that MOR1D in the spinal cord signals by activating the itch-producing receptor for gastrin-releasing peptide (GRP).
The results suggest that inhibiting the MOR1D-GRP receptor interaction could block opioid-induced itch without sacrificing pain relief. Further, the discovery of a μ-opioid receptor subtype responsible for itch raises the alluring prospect that additional variants might be responsible for other side effects.
Itch commonly results from opioids administered spinally, either by epidural or intrathecal injection. It is thought that itch and analgesia are two sides of the same coin—when opioids block pain, they somehow unmask itch signals. But other evidence suggests that the two effects might not be so tightly intertwined. For example, the Chen group saw that when they administered morphine to mice by intrathecal injection, scratching behaviors started soon after treatment but tapered off within 15 minutes, whereas analgesia held steady for at least an hour. Further, they found that mice repeatedly dosed with morphine became tolerant to the analgesic effects of the drug, but still developed morphine-induced itch.
Morphine’s painkilling properties and side effects are all mediated by the μ-opioid receptor, so how to explain the divergence between itch and analgesia? One possibility is receptor subtypes: At least 20 MOR1 subtypes are expressed in mice, a result of alternative splicing from a single gene (Pasternak, 2010). To find out if pain relief and itch depend on different receptor isoforms, the researchers knocked down specific subtypes using exon-specific small interfering RNAs (siRNAs) delivered into the spinal cord. They discovered that reducing expression of the MOR1D isoform inhibited morphine-induced itch, but did not block pain relief.
“Our study is the first to show that there is one isoform that is not involved in opioid analgesia at all,” Chen said. Now, he wonders what the other isoforms could be doing. “It’s completely possible that they may mediate other side effects.”
The team also investigated the mechanism by which MOR1D mediates opioid-induced itch. In previous work, they had identified the GRP receptor (GRPR) as a mediator of itch triggered by peptide release in the spinal cord from primary afferents (Sun and Chen, 2007; Sun et al., 2009). In their new study, the researchers found that GRPR also mediates itch triggered by morphine. In the dorsal horn of the spinal cord, MOR1D colocalized with GRPR; MOR1, on the other hand, appeared to be expressed in different neurons. Co-immunoprecipitation showed that MOR1D and GRPR physically interact. Further, morphine binding to MOR1D led to internalization of both MOR1D and GRPR, and activated downstream signaling from GRPR. Now, Chen said, the group is interested in learning more about the crosstalk between these two receptors, including the possibility that not only the receptors themselves, but also their intracellular signaling pathways, interact.
Could MOR1D serve as a therapeutic target to relieve opioid-induced itch? MOR1D is distinguished from other μ receptors by a seven-amino-acid segment at its C-terminus, which Chen and his colleagues thought might be required for interaction with GRPR. When they injected a synthetic peptide containing the motif into the spines of mice, they found that it disrupted the interaction of GRPR with MOR1D and prevented morphine-induced itch, but not analgesia.
Blocking the GRPR-MOR1D interaction “is a logical, albeit challenging, strategy [for attenuating opioid-induced itch], as very few approved drugs specifically target protein-protein interactions,” wrote Takashi Miyamoto and Ardem Patapoutian, Scripps Research Institute, La Jolla, California, in a review accompanying the paper.“As an alternative, many of the molecular components in the opioid-induced itch pathway…may be additional candidate targets for specifically attenuating itch.”
Other targets, other problems?
In another new paper, Esther Krook-Magnuson and colleagues at the University of California, Irvine, identify a new class of target cells for opioid action in the brain. The study, published in the October 19 Journal of Neuroscience, reveals fundamental information that could help in separating the painkilling properties of opioids from their brain-based side effects. The authors note that the cells they identify, the neurogliaform family of interneurons, are found in many parts of the brain. They write, “Modulation of the neurogliaform family by μORs across brain structures, should that be found in future studies, would have sweeping consequences, relevant to a wide spectrum of processes and behaviors, including learning and reward processing.”
In the study, Magnuson and coworkers looked specifically in area CA1 of the hippocampus, where some interneurons are already known to express MORs. They found that another major class of interneurons in the CA1, Ivy and neurogliaform cells, also respond to MOR activation. In electrophysiological recordings from rodent hippocampal slices, the researchers showed that μ-opioid receptor agonists inhibited cell functions, including the release of the inhibitory neurotransmitter GABA and the induction of persistent firing in Ivy cells. Given that Ivy cells were discovered only recently (Fuentealba et al., 2008), there is clearly a lot left to learn about the role these cells play in opioid responses.
Comments
Akihiko Ikoma, University of California San Francisco
In the present study, Chen ZF
In the present study, Chen ZF and his colleagues have again successfully differentiated itch from pain by their elegant experimental methods, which definitely has a significant impact on the understanding of balance between itch and pain. The so-far accepted hypothesis that decreased pain would cause itch now needs to be revised. As the authors have described, analgesic agents that work only on MOR1 but not on MOR1D might be able to inhibit pain without adverse itch induction, which will bring about a great therapeutical benefit. Heterodimerization of MOR1D with GRPR rouses my interest in the interaction between GRPR and kappa opioid receptor (KOR), since KOR agonists have been demonstrated to be antipruritic.