Signal stopper

BLOOMINGTON, Ind.—Neuropathic pain—the chronic, pathological pain that continues even when the cause of the pain has been removed—can be caused by damage to nerve cells, as well as by medicines used to treat cancer. This issue is very common, affecting 5 to 10 percent of people worldwide, and no cures or effective treatments are currently available. Chemotherapy-induced pain can be so intense that it causes some cancer patients to stop treatment and others to suffer damaging side effects.

A collaboration between research groups from Indiana University and the Turku Centre for Biotechnology in Finland has collaborated in discovering an experimental molecule that appears to interrupt the signaling cascades in the body that cause multiple forms of neuropathic pain without producing unwanted side effects. The study was reported in the May 2018 issue of the journal Pain. The research was funded by the National Institutes of Health's National Cancer Institute.

The researchers, who met at a Society for Neuroscience meeting, were led by Andrea Hohmann of Indiana University and Michael Courtney from the Turku Centre for Biotechnology. Hohmann explained that the approach offers potential for maximizing the therapeutic efficacy of novel inhibitors likely to exhibit favorable analgesic profiles without the unwanted side effects of conventional treatments on motor function or memory.

The molecule described in the study targets a glutamate receptor called N-methyl-D-aspartate receptor (NMDAR). Previous experimental drugs used to block the NMDAR receptor caused side effects such as memory impairment and motor dysfunction, thus limiting their therapeutic potential. In the study, which was performed with mice, the designer molecule used did not cause negative side effects nor typical motor side effects observed with previous experimental molecules that directly target NMDARs.

According to Hohmann, chemotherapy-induced peripheral neuropathy, which can be permanent, limits life-saving anticancer treatment and negatively impacts quality of life. By understanding the critical signaling pathways involved in development and maintenance of the neuropathy, researchers can find therapeutic strategies to prevent or treat it. The NMDAR signaling complex plays a vital role in central sensitization of chronic pain. While NMDAR antagonists are effective in reducing pain sensitization, they disrupt normal physiological processes, such as motor function, memory and cognition. The NMDAR signaling complex consists of many protein partners including the scaffold postsynaptic density 95 kDA (PSD95) protein, the neuronal enzyme nitric oxide synthase (nNOS) and its adaptor protein NOS1AP. By disrupting specific steps downstream of NMDAR activation, it is possible to reduce pain sensitization while eliminating side effects associated with upstream receptor blockade.

The study’s goal was to block signals caused by the binding of nNOS to the protein NOS1AP during the process of neurotransmission, as a new approach to treating chronic pain. NOS1AP is present in fine structures of living neurons, including structures that may be synaptic spines.

The team in Finland designed the molecule after discovering that NOS1AP, which is downstream of nNOS, triggers several biological pathways that are associated with abnormal glutamate signaling, including neuropathic pain. That molecule gave the Indiana University group the tools to ask questions about suppressing pain, Hohmann explained.

The Indiana University group showed that an experimental molecule designed by the Turku group to prevent nNOS signaling to NOS1AP reduced two forms of neuropathic pain in rodents. These forms of pain usually develop because of the chemotherapeutic agent paclitaxel or nerve damage.

The treatment also disrupted markers of nociceptive signaling in the spinal cord when the test drug was injected at that site into mice.

“Importantly, the chemical that prevents this signaling did not cause the negative side effects observed in previous experiments,” Hohmann said. “Our studies suggest that the nNOS-NOS1AP interaction site is a previously unrecognized target for pain therapies.”

“The results imply that the protein NOS1AP might be a valuable novel target in the development of more effective medicines to treat neuropathic pain,” Courtney added. “NOS1AP should be studied in more detail to find the best way to prevent this protein from contributing to chronic pain.”