Studies by Hokkaido University researchers have identified the neural circuitry involved in chronic pain-induced maladaptive anxiety in mice. Their studies showed that chronic pain leads to a neuroplastic change that suppresses the neuronal pathway projecting from a region of the brain called the bed nucleus of the stria terminalis (BNST), to the lateral hypothalamus.

They suggest that the findings could have clinical implications and potentially lead to the development of new treatments for chronic pain and pain-related psychiatric disorders such as anxiety disorders and major depressive disorder. “Clinicians have known for a long time that chronic pain often leads to anxiety and depression, however the brain mechanism for this was unclear,” said Masabumi Minami, PhD, at the Faculty of Pharmaceutical Sciences at Hokkaido University, who is corresponding author of the team’s published paper in Science Advances. “These findings could not only lead to improved treatment of chronic pain, but also to new therapeutics for anxiety disorders.” The report by Minami and colleagues is titled “Chronic pain–induced neuronal plasticity in the bed nucleus of the stria terminalis causes maladaptive anxiety,” in which they concluded, “The current study sheds light on the neuronal mechanisms underlying psychiatric disorders associated with chronic pain.”

Pain is essential to survival because it functions as what the authors describe as “a biological alarm” for impending or actual tissue damage. However, they further noted, “chronic pain is a persistent, inescapable stress, which leads to maladaptive emotional states.” Chronic pain is often comorbid with psychiatric disorders, such as depression and anxiety disorders, but while this association has long been recognized, the underlying mechanisms aren’t well understood, the authors continued. So while it is thought that chronic pain causes changes in neural circuits, giving rise to depression and anxiety, as the Hokkaido University researchers further pointed out, “ … brain areas of neuronal plasticity that lead to psychiatric disorders remain to be elucidated.”

For their reported study the scientists looked at how neuronal circuits were affected by chronic pain in experimental mice. Their studies focused on a forebrain BNST, which has been implicated in negative emotional states, such as anxiety and fear. This area of the brain receives both direct and indirect pain information from the spinal dorsal horn.

The team’s previous work had demonstrated that chronic pain increased inhibitory inputs to BNST output neurons projecting to a part of the brain known as the ventral tegmental area (VTA), and suppressed VTA dopaminergic neuron activity. But it wasn’t known whether increased inhibitory inputs to BNST output neurons are involved in chronic pain–induced anxiety-like behavior, nor is the neuronal mechanism for the increased inhibitory inputs during chronic pain understood.

To address these questions, the investigators carried out behavioral and electrophysiological analyses using chemogenetic and optogenetic techniques in an experimental mouse model of pain, to manipulate the neuronal activity of a specific population of BNST neurons. “Since selective activation of the anterodorsal BNST (adBNST) output neurons projecting to the lateral hypothalamus (LH) has been reported to produce an anxiolytic effect, we examined whether the persistent increase in inhibitory inputs to LH-projecting adBNST neurons was involved in anxiety-like behavior observed in chronic pain model mice,” they explained.

When the team measured the activities of the target neurons in mice after four weeks of chronic pain, they found that the chronic pain had caused a neuroplastic change that suppressed the neuronal pathway projecting from the BNST to the lateral hypothalamus. “… electrophysiological and behavioral analyses using chemogenetic manipulation of neuronal activity demonstrated that chronic pain increased inhibitory synaptic inputs to LH-projecting adBNST neurons, which in turn induced maladaptive anxiety,” the team noted. “Chemogenetic manipulation revealed that sustained suppression of LH-projecting BNST neurons played a crucial role in chronic pain–induced anxiety.”

Neuronal circuit involved in chronic pain-induced maladaptive anxiety. Increased excitability (white arrow) of BNSTCART neurons causes a sustained suppression (black arrow) of LH-projecting BNST neurons during chronic pain, thereby enhancing anxiety-like behavior (Naoki Yamauchi, et al. Science Advances. April 27, 2022). [Naoki Yamauchi, et al. Science Advances. April 27, 2022]
More specifically, their experiments showed that chronic pain increased the excitability of a specific subpopulation of BNST neurons that express cocaine- and amphetamine-regulated transcript (CART). “The elevated excitability of CART-positive neurons caused the increased inhibitory inputs to LH-projecting BNST neurons, thereby inducing anxiety-like behavior,” they further stated. Using chemogenetics—an advanced technique to manipulate neuronal activity—the investigators also showed that restoration of the suppressed activity of the neuronal pathway attenuated the chronic pain-induced anxiety.


The results indicate that chronic pain-induced functional changes in the neuronal circuits within the BNST lead to maladaptive anxiety. “The results suggest that chronic pain elevated the excitability of a genetically identified subpopulation of BNST GABAergic neurons, thereby increasing the inhibitory inputs to LH-projecting adBNST neurons, which induced anxiety-like behavior,” they concluded. “These findings demonstrate how chronic pain–induced neuroplastic changes induce psychiatric disorders characterized by maladaptive anxiety.”

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