Discovery Suggests Potential New Target for Pain Control

Blocking the signaling pathway IRE1α-XBP1, which is an important regulator of many cell functions, may offer a less opioid-dependent way of treating pain.

Scientists have discovered a previously unknown mechanism in mice that influences their ability to feel pain. The discovery suggests the possibility of new approaches to treating pain in humans that are an alternative to opioid drugs.

The scientists, reporting in the journal Science, found that the production of prostaglandins in white blood cells depends on a signaling pathway known as IRE1α-XBP1, which is an important regulator of many cell functions. Prostaglandins are substances that influence an array of processes including pain perception.

The scientists found that when the IRE1α-XBP1 pathway was knocked out in the white blood cells of mice, prostaglandin synthesis was impaired. Consequently, the investigators showed, because of low levels of prostaglandins, the animals’ perception of pain was reduced.

“The pharmacological modulation of IRE1α-XBP1 signaling may represent an alternative approach for pain control, with the potential of producing better analgesia, diminished opioid requirements, and reduced opioid side effects,” said the authors. Laurie H. Glimcher, MD, president and CEO of Dana-Farber, is a co-corresponding author of the report. Lead senior author is Juan R. Cubillos-Ruiz, PhD, of Weill Cornell Medical College.

Laurie H. Glimcher, MD.

The findings being reported in Science were a byproduct of experiments designed not to study pain perception but to elucidate the function of IRE1α-XBP1 signaling in leukocytes — the white or colorless blood cells, also known as myeloid cells, many of which have an immune function.

IRE1α-XBP1 signaling is part of a cellular response to stress known as the unfolded protein response. This response is important in maintaining immunity and other cellular functions, and Glimcher and others have made an array of discoveries about various roles of IRE1α-XBP1 signaling in different types of cells. For example, they recently identified a role for the pathway in natural killer cells. However, not much has been known about this signaling pathway’s function in leukocytes.

To explore this question, the researchers “knocked out” IRE1α and noted thousands of other genes whose activity was altered as a result. Among the genes whose activity was lowered in the absence of IRE1α were prostaglandin-endoperoxide synthase 2 (Ptgs2/Cox-2) and prostaglandin E synthase (Ptges/mPGES-1). Both of these substances are rapidly made in cells in response to inflammatory stimuli — which are sensed by IRE1α. The experiments showed that without IRE1α-XBP1 signaling, prostaglandins are made at much lower levels.

It was previously known that the two prostaglandins are necessary for sensory nerve cells to respond to pain. The scientists postulated that mice lacking IRE1α in their leukocytes, and therefore unable to generate appropriate levels of prostaglandins in response to inflammation, would demonstrate reduced pain behaviors. This turned out to be true.

The authors described this as an “unexpected function” for IRE1α “as a central mediator of prostaglandin biosynthesis and behavioral pain responses in mice.”

This unexpected result, they added, suggests the need for further studies “to determine whether IRE1α-XBP1 signaling also regulates additional physiological and pathological processes driven by prostaglandins such as pregnancy, fever, allergy, and immunosuppression in cancer.”

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