Researchers have discovered new insights about pain transmission in neurons, which could aid in the development of alternatives to opioids and more effective analgesics. Chronic pain afflicts roughly one fifth of people at some point in their lives, and existing therapies often fail to offer sufficient relief or produce dangerous and undesirable side effects - as highlighted by skyrocketing rates of medication-induced death associated with the current opioid epidemic. One class of cellular receptors, called GPCRs, control all steps of pain transmission, but most GPCR-targeted analgesic drugs have failed in clinical trials for reasons that have remained mysterious. GPCRS are typically thought to exert their effects from the surfaces of cells by relaying information from the outside-in, and here, Dane Jensen et al. found that a GPCR called substance P neurokinin 1 receptor (NK1R) also signals from the inside of neurons to sustain their excitation and transmit pain. Preventing NK1R internalization alleviated pain in rats, but such a therapeutic strategy would likely interfere with important physiological processes in humans. To overcome this obstacle, the researchers targeted signaling inside the cell by coupling NK1R inhibitors to special molecules called cholestanols, which provided prolonged pain relief in rats - the analgesic effects of the modified compounds lasted four to six times longer as compared to surface-acting agents. The authors say the inability of previous drugs to effectively reach NK1R inside the cell could have contributed to their lack of clinical success, and that a new paradigm of drug delivery targeting of internalized GPCRs might offer better treatments for chronic pain.