Chronic pain often leads to depression, which US researchers have addressed using a mechanism potentially involving ketamine.
A study from the University of Alabama at Birmingham, USA, has uncovered the underlying mechanisms leading to chronic pain-induced depression, and identified potential therapeutic targets using ketamine as an antidepressant.
Chronic pain often leads to depression, which makes the pain worse and harder to treat medically. The mechanism that causes depression involves over-sensitivity in a part of the brain called the anterior cingulate cortex (ACC).
Ketamine is a drug known to produce acute and sustained antidepressant-like effects in chronic pain-induced depression, without reducing sensory hypersensitivity. Ketamine’s persistent antidepressant-like effects work by inhibiting Tiam1-dependent neurons.
Research, published in Journal of Clinical Research, focuses on a protein called Tiam1, which modulates the activity of other proteins that help build or unbuild cells’ cytoskeletons. They found that chronic pain in a mouse model leads to activated Tiam1 in ACC pyramidal neurons, resulting in an increase in the number of spines on neural dendrites.
This higher spine density increased the number of connections between neurons, and the strength of those connections—a change known as synaptic plasticity. Those increases caused hypersensitivity and were associated with depression in a mouse model. Reversing the number and strength of connections in the model, using an antagonist of Tiam1, reduced the mice’s depression and hypersensitivity of neurons.
To show that Tiam1 in the ACC modulates chronic pain-induced depression-like behavior, the researchers used molecular scissors to delete Tiam1 from rat forebrain excitatory neurons. These mice were viable, fertile, and exhibited no gross changes, and they still showed hypersensitivity to chronic pain.
However, these Tiam1 conditional knockout mice did not exhibit depression- or anxiety-like behavior in five different tests measuring depression or anxiety.
When Tiam1 was specifically deleted from ACC neurons, they found similar results to the broader forebrain deletion. Thus, Tiam1 expressed in ACC neurons appears to specifically mediate chronic pain-induced depression-like behavior.
Changes in dendritic neurons in the ACC for chronic pain-induced depressive-like behavior—the team observed a significant increase in dendritic spine density and signs of increased cytoskeleton building. This was accompanied by increased NMDA receptor proteins and increased amplitude of NMDA currents in ACC neurons, both associated with hyperactivity.
These deleterious changes were not observed in Tiam1-knockout mice.
The researchers further showed that blocking Tiam1 signaling with a known inhibitor reduced chronic pain-induced depression-like behavior without reducing chronic pain hypersensitivity. Inhibition also normalized dendritic spine density, cytoskeleton building, NMDA receptor protein levels and NMDA current amplitude.
Sustained antidepressant-like effects of ketamine in chronic pain are mediated, at least in part, by ketamine blocking Tiam1-dependent, maladaptive synaptic plasticity in mouse ACC neurons.
“Our work demonstrates the critical role that Tiam1 plays in the pathophysiology of chronic pain-induced mood dysregulation and the persistent antidepressant-like effects of ketamine, revealing it as a potential therapeutic target for the treatment of comorbid mood disorders in chronic pain.” said Dr. Lingyong Lee, associate professor at the University of Alabama at Birmingham’s Department of Anesthesiology and Perioperative Medicine.