Researchers have found a new way to block a root cause of pain. The key is a naturally occurring protein called apolipoprotein A-I binding protein (AIBP). AIBP binds to toll-like receptor 4 (TLR4), a protein that sits on the surface of cells like an antenna, searching for signs of infection or tissue damage. The researchers found that treating mice with a single spinal injection of AIBP -- and thus switching TLR4 "off" -- prevented and reversed inflammation and cellular events associated with pain processing.

As reported in Cell Reports, the treatment alleviated chemotherapy pain in mice for two months with no side effects.

"Opioids and most other pain medications simply dampen a person's perception of pain. But the source of the pain is still there," said co-senior author. "At the same time, opioids also impart a feeling of pleasure, which leads to their misuse and addiction. What's so special about our new approach, inhibiting the TLR4 receptor with AIBP, is that it actually modifies the pain processing systems themselves. So, if you think of neuropathic pain as a disease, then we see this as truly disease-modifying. We're blocking the underlying mechanism that causes pain, not just masking the symptoms."

In laboratory tests, the researchers discovered that AIBP inhibited TLR4 by removing cholesterol from lipid rafts -- cholesterol-rich areas of a cell's membrane that help control how cells communicate with each other and their environments. In mice, spinal (intrathecal) injections of AIBP reduced lipid rafts in central nervous system immune cells called microglia. The injections also reduced TLR4 dimerization, microglial activation and inflammation in the spinal cord.

After chemotherapy, humans and animals often develop persistent states of pain in response to even the lightest touch. In this study, mice that received chemotherapy reacted to the lightest touch. But a single intrathecal injection of AIBP completely reversed the chemotherapy-induced pain state and the mice were able to endure normal levels of mechanical stimulation. This pain-relieving effect lasted for two months and the AIBP injection did not affect motor functions.

"We are working on ways to deliver AIBP systemically, but if it comes down to a choice between living with chronic pain or getting a spinal injection once every few months, we think most people would take the injection," other co-senior author said. "As it stands now, AIBP could be developed as therapy for unremitting severe pain that only responds to high dose morphine. AIBP would remove the need for opioids, and reduce the potential for drug abuse."

According to the co-senior author, of the 1.7 million patients who receive a cancer diagnosis each year, it is estimated that at least 39 percent experience pain in the course of the cancer and after treatment. If each of those patients takes an average 100 milligrams of morphine or its equivalent per day for one year, an estimated morphine burden would be approximately 24,000 kilograms per year -- and that's just for patients with cancer.

"We're not saying we shouldn't use opiates to treat chronic pain or in particular cancer pain -- that would be a tragedy," co-senior author said. "But it would also be a greater tragedy if we didn't support work to find a substitute for systemic opiates ... if for no other reason to reduce its presence in our society."

http://ucsdnews.ucsd.edu/pressrelease/single_injection_alleviates_chemotherapy_pain_for_months_in_mice

https://www.cell.com/cell-reports/abstract/S2211-1247(18)30710-1