Brainstem Opioid Receptors Act as a Brake on Chronic Pain

Nearly a quarter of adults in the US live with chronic pain.¹ For those affected, everyday aches and shooting, burning, stinging sensations can be compounded by hypersensitivity to light, touch and sound, making daily life even more challenging.

According to a statement by neuroscientist Jordan McCall from Washington University School of Medicine in St. Louis, “The pain is difficult to treat, and traditional opioid medications bind to receptors throughout the entire body and brain, often leading to side effects, tolerance and addiction risk.”

To circumvent this problem, McCall and his team focused on the locus coeruleus (LC), a small region in the brainstem that contains a cluster of cells in the involved in regulating pain signals and stress responses. Under normal conditions, the LC can help dial down pain signals.² But nerve damage can push this system into overdrive, causing the LC to, instead of suppressing pain, amplify pain signals and contribute to chronic pain.³

In a new study, published in Current Biology, McCall and his colleagues found that mu opioid receptors, when activated in this brain region, tamp down pain.⁴ Mu opioid receptors bind to the body’s naturally produced opioids, like endorphins, or synthetic ones such as morphine, to control pain. So, without these receptors, mice with neuropathic pain became even more sensitive to touch and heat. These findings may help researchers develop new, targeted therapies for chronic neuropathic pain.

Given LC’s contradictory role in suppressing acute pain but amplifying chronic pain, the researchers assessed the brain region’s activity in these conditions in mice. To do this, the team first silenced LC neurons using an inhibitory optogenetic approach. Turning off LC neurons resulted in reduced sensitivity to touch and heat among unstressed animals compared with the control group. For instance, these mice could withstand higher degrees of physical force applied to their hindpaws and it took longer to remove a paw when placed on a temperature-controlled hot plate.

However, this acute response changed when mice received a neuropathic injury to the lower hind leg. The researchers observed that LC inhibition dampened pain stimuli in the first week, but this inhibition gradually caused the mice to experience prolonged sensitivity in their injured limb.

Aside from this exogenous LC inhibition, the researchers homed in on the endogenous mu opioid receptors (MOR), which are abundant in the LC, to examine their role in pain regulation. When activated, MOR lessened pain throughout the nervous system. In contrast, LC-MOR deletion in mice with neuropathic pain caused the mice to become even more sensitive to touch and heat. Restoring these receptors reversed the hypersensitivity, suggesting that these receptors are the biological switch that can shut off chronic pain. Thus, a disruption of LC-MOR activity can convert this brain region into a pain generator, contributing to chronic pain.

The researchers acknowledged that more in-depth studies need to be conducted. “Understanding how localized receptors in the locus coeruleus act as gatekeepers could lead to more targeted, effective pain therapies with fewer risks,” explained McCall in the statement.