When patients take opioid drugs such as morphine to treat chronic pain, they often develop tolerance to the medication, needing higher and higher doses to get relief. Some researchers think this is caused, in part, by opioid-induced hyperalgesia (OIH)—a hypersensitivity to pain brought on by long-term use of the drugs. Now researchers report an orally active compound that blocks this effect in mice, possibly leading to a therapeutic that lessens opioid side effects (ACS Chem. Neurosci. 2015, DOI: 10.1021/cn500219h). Previously, Frédéric Simonin of the University of Strasbourg, in France, and colleagues developed an acylated dipeptide that prevents OIH by inhibiting neuropeptide FF receptors. These receptors tune down opioid receptor signaling in the brain. In the new study, the team examined the structure-activity relationship of the dipeptide to design a more druglike compound based on a derivative of the positively charged amino acid ornithine. When the researchers gave mice a saline solution containing the compound followed by a large dose of the opioid fentanyl, the animals showed no signs of OIH. But animals getting a sip of saline alone, before the opioid, started to have heightened pain sensitivity within a day.