YAMASHITA Hidetoshi ≪Molecular Neuroscience≫ “Dorsal horn interneuron-derived Netrin-4 contributes to spinal sensitization in chronic pain via Unc5B.”
Publish The Journal of Experimental Medicine（2016） doi:10.1084/jem.20160877
Neuropathic pain is refractory, chronic pain caused by illnesses or disorders such as nerve damage, diabetes and stroke. A group of researchers has discovered that the protein Netrin-4 is secreted from spinal interneurons and amplifies pain. Animals deficient in Netrin-4 did not demonstrate pathological pain due to a neurological disorder. Furthermore, strong, continuous analgesic effects were observed when Netrin-4 was suppressed in animals experiencing neuropathic and inflammatory pain. The results will lead to the development of novel treatments for neuropathic pain.
【Background (including information on researchers)】
Chronic pain affects 14-23% of the Japanese population (approximately 20 million people) according to a recent survey. Worldwide, there are estimates that more than 1.5 billion people suffer from chronic pain. In the United States, chronic pain is a major social issue, responsible for an economic loss of an estimated 900 million yen (~$9 million). However, no more than one quarter of patients are satisfied with current treatments. Due to the lack of efficacy and side effects of current medications, there is an extremely high medical demand for novel, efficient, and therapeutic drugs to relieve pain.
Neuropathic pain is refractory, chronic pain caused by illnesses or disorders such as nerve damage, diabetes and stroke. Sensory information from the skin and internal organs reaches the spine through peripheral nerves (Figure 1). Sensory information is modified and integrated in the dorsal column of the spinal cord and is then transmitted to the brain through secondary sensory nerves, resulting in the sensation of pain. One of the major causes of neuropathic pain is thought to be abnormal excitement of the nerves in the dorsal column.
There are a number of hypotheses regarding pain-related mechanisms in the central nervous system; while these hypotheses have served as the basis for attempts at developing analgesic drugs, little progress has been made. In these pain mechanism hypotheses, interneurons are considered to play a major role in amplifying pain in the dorsal column, which serves as an important pain signal transduction and relay site. The molecular basis of these interneurons has remained unknown for a long time and has not been approached as a target for analgesic drugs.
The research group of Professor Toshihide Yamashita and former Specially Appointed Assistant Professor Yasufumi Hayano (currently a postdoctoral fellow at the Max Planck Florida Institute for Neuroscience) et. al, at Osaka University Graduate School of Medicine’s Department of Molecular Neuroscience, has discovered for the first time that the protein Netrin-4 is secreted from spinal interneurons and amplifies pain.
【Address to society】
First, the research group discovered that Netrin-4 is expressed specifically in interneurons of the dorsal column. Next, in order to verify the role of Netrin-4, they induced peripheral nerve disorders in Netrin-4 knockout rats. Hyperalgesia occurs in normal rats, but was not observed in Netrin-4 knockout rats (Figure 2 (1)). Also, when rats given a peripheral nerve disorder and exhibiting hyperalgesia were administered antibodies to suppress Netrin-4 function or nucleic acid to reduce Netrin-4 expression, continuous, strong analgesic effects were observed. Conversely, hyperalgesia occurred when Netrin-4 was administered intrathecally (Figure 2 (2)). Similar analgesic effects were also observed in rats given inflammatory pain. The above results led to the world’s first discovery that Netrin-4 is the molecule responsible for the pain mechanism.
Further analysis demonstrated that Netrin-4, which is secreted from dorsal column interneurons, binds with Unc5B receptors, which are expressed in pain-conveying secondary sensory nerves, to induce excitement in these nerves, thereby causing neuropathic pain (Figure 3). They were thus able to elucidate the mechanism by which Netrin-4 amplifies pain.
Thus, Netrin-4 inhibitors demonstrate potential as a highly effective and highly safe breakthrough treatment for the many chronic pain patients for whom current drugs are inadequate.
【Comments/messages from researcher(s)】
We anticipate that the results of this research will lead to development of novel treatments for neuropathic pain.
【Bibliographic and funding information】
Journal: The Journal of Experimental Medicine
Title: Dorsal horn interneuron-derived Netrin-4 contributes to spinal sensitization in chronic pain via Unc5B.
Authors: Yasufumi Hayano, Keiko Takasu, Yoshihisa Koyama, Moe Yamada, Koichi Ogawa, Kazuhisa Minami, Toshiyuki Asaki, Kazuhiro Kitada, Satoshi Kuwabara, and Toshihide Yamashita
Funded by: This work was supported by a Grant-in-Aid for Scientific Research (S) from the Japan Society for the Promotion of Science (JSPS) (25221309).