How do you treat chronic pathological pain? Right now, the best option involves the use of a class of powerful painkillers — opiates — that are often addictive and can produce harmful side effects.
However, there may be a new option for chronic pain. Researchers at Hopkins have identified a class of receptors (complex proteins in the body that receive and “process” chemical signals), the Mas-related G-protein-coupled receptors (Mrgprs), that may be useful targets for future painkillers. Studies in mice suggest that a compound that selectively activates Mrgprs may be able to reduce chronic pain with minimal side effects.
“Mrgprs may be compelling new pain-specific targets for pain therapy by virtue of their restricted distribution in nociceptive afferent sensory neurons,” Yun Guan, an assistant professor of Anesthesiology and Critical Care Medicine at Hopkins, said.
Nociceptive afferent sensory neurons carry pain signals from the body to the brain. Since the Mrgprs are only found there, it seems likely that they are involved in how we sense pain. “However, the roles of Mrgprs in sensory processing of pain, especially pathological pain, remain unclear,” Guan said.
In order to better understand the role of Mrgprs in pain signaling, Xinzhong Dong, Assistant Professor of Neuroscience at Hopkins School of Medicine, developed a line of Mrgpr-knockout (KO) mice, which do not express the Mrgprs. “KO mice show prolonged mechanical and thermal pain hypersensitivity after hind paw inflammation, compared to wild-type (WT) littermates,” Guan said, something he demonstrated in an earlier study. Wild-type mice are ordinary mice, with functional Mrgprs; that KO mice were more sensitive to pain after inflammation than WT mice shows that Mrgprs are involved in pain signaling.
More recently, Guan found that knocking out the Mrgprs enhances the response of certain neurons, which subsequently triggers central pain sensitization. He also found that KO mice had no response to bovine adrenal medulla peptide 8-22 (BAM 8-22), a compound that activates the MrgprC receptor and acts as a painkiller.
Further, Guan found that when BAM 8-22 was administered to the normal mice, the neurons expressed a significantly attenuated response. However, this effect was eliminated in KO mice.
“Members of the Mrgpr family, in particular MrgprC, may constitute a novel endogenous inhibitory mechanism for regulating persistent pain in mice,” Guan said. In short, activating MrgprC seems to reduce chronic pain.
Compounds that selectively activate the Mrgprs should have few side effects, since the Mrgprs are only expressed in a highly specific region of the brain. In contrast, opiates have wide-reaching neurological effects.
“Opiates bind to receptors that are widely expressed throughout the central nervous system, so dose-limiting adverse effects like sedation and cognitive dysfunction, and perceived risks of addiction and abuse, present substantial barriers to their clinical use,” said Guan.
Drugs that target receptors expressed widely will have more side effects than drugs that target receptors expressed in highly specific locations.
More work still needs to be done. “Additional functional and mechanistic studies are needed to elucidate details of Mrgpr-mediated pain-inhibitory mechanisms in chronic pain setting, Guan said. The specific function of the Mrgpr in pain signaling, and the mechanism by which it acts to inhibit pain, needs to be determined.
Guan plans to conduct further studies into the Mrgpr, which would contribute to future high-throughput screening for new agonists (compounds that activate a receptor) of the MrgprX1 receptor, which is the equivalent of MrgprC in humans. These agonists may be useful drugs for patients who respond poorly or develop tolerance to opiate-based painkillers.
