Chronic pain and anxiety disorders are often linked, and changes in the brain’s neural circuits may be a driver of this relationship, according to findings from an animal study model.
Although pain serves as “a biological alarm” for impending or actual damage to the body, which many clinicians describe as “fight or flight” to their patients, chronic pain in a persistent stressor that leads to maladaptive emotional states, including depression and anxiety disorders , wrote Naoki Yamauchi, PhD, of Hokkaido University, Sapporo, Japan, and colleagues in their paper.¹
Preclinical studies using animal models of chronic pain have shown depression and anxiety-like behaviors, which suggest “that chronic pain causes plastic changes in neural circuits and gives rise to negative emotions, such as depression and anxiety,” the researchers noted. However, the mechanism behind this association remains unclear, they wrote.
Are Brain Pathways in People with Chronic Pain Primed for Anxiety?
In their study, published in Scientific Advances, Yamauchi et al used a mouse model to examine how brain pathways may be involved in the development of anxiety in the context of chronic pain. Specifically, they used electrophysiology to measure the activities of neurons in the brains of mice who were subjected to 4 weeks of chronic pain.¹
Their fndings: chronic pain was associated with a particular neuroplastic change initiating in the region of the brain know as the bed nucleus of the stria terminalis (BNST). Chronic pain suppressed activity of the neuronal pathway from the BNST to the lateral hypothalamus (LH). They defined BNST as “a forebrain structure implicated in negative emotional states, such as anxiety and fear,” that is known to be associated with maladaptive anxiety.
Yamauchi and team also confirmed the association between anxiety and pain using chemogenetics, a technique that manipulates neuronal activity, to restore the activity of the neuronal pathway that had been suppressed by chronic pain. This restoration attenuated the maladaptive anxiety brought on by the pain.
In addition, the researchers used molecular genetics to show that chronic pain enhanced the activity of a subset of BNST neurons that express cocaine- and amphetamine-regulated transcript (CART). The elevated excitability” of these particular neurons contributed to the inhibition of BNST neurons to the LH, and induced anxiety-like behavior, the researchers stated.
Overall, these results “suggest that sustained inhibition of LH-projecting anterodorsal BNST (adBNST) neurons plays a critical role in chronic pain-induced anxiety-like behavior.”¹
The findings were limited by the use of a mouse model, and the specific neuronal mechanisms behind chronic pain-induced depression and anxiety have yet to be fully explained, the researchers wrote in their paper. However, they were able to demonstrate that manipulation of adBNST neurons induces psychiatric disorders characterized by maladaptive anxiety and offers a basis for further research.
Examining the neurobiology of pain is always helpful and “especially when the brain mechanism for [the findings] was unclear,” said David Cosio, PhD, ABPP, a psychologist at the Jesse Brown VA Medical Center in Chicago. “However, remember we are still talking about how this affects mice, not humans,” he noted.
dr. Cosio said that he was not especially surprised by the findings. “We already know that there is a strong relationship between anxiety and chronic pain,” he said. “In fact, newer studies suggest that anxiety disorders may be present in up to 60% of patients with chronic pain.”
What is new is that, “these findings suggest one way that chronic pain-induced functional changes in the neuronal circuits can lead to maladaptive anxiety,” said Dr. cosio. However, more research is needed, and “finding the same changes in humans would be the next logical step,” he noted.
Lord, Drs. Cosio and Demyan discuss how to manage maladaptive anxiety in people with chronic pain.
Disclosures: The study was supported by Grant-in-Aid for Scientific Research (B) and for Challenging Research (Exploratory), Grant-in-Aid for JSPS Fellows from the Japan Society for the Promotion of Science (JSPS), and the Japan Agency for Medical Research and Development (AMED).
- Yamauchi N et a. Chronic pain-induced neuronal plstiity in the bed nucleaus of the stria terminalis causes maladaptive anxiety. Sci Adv. 2022 Apr 29. doi: 10.1126/sciaadv.abj5586. Epub 2022 Apr 27.