Multiple modulatory roles of serotonin in chronic pain and injury-related anxiety

Front. Synaptic Neurosci., 2023 · DOI: 10.3389/fnsyn.2023.1122381 · Published: April 18, 2023

Simple Explanation

Chronic pain can lead to side effects like anxiety and depression, impacting quality of life. Serotonin (5-HT) in the brain regulates pain, cognition, and emotions. This review explores how 5-HT acts on chronic pain and anxiety related to injuries, focusing on the brain mechanisms involved. Serotonin, a key neurotransmitter, has been recognized as a key modulator in pain processing and potential targets for pain treatment. The 5-HT system exerts diﬀerent regulations of pain perception and anxiety in diﬀerent ways, with many agonists/antagonists of 5-HT receptors used to treat pain- and anxiety-related conditions as the ﬁrst-line drugs This review summarizes the neural pathways and receptor distribution of the 5-HT system associated with chronic pain and injury-related anxiety, and describes its pathophysiologic roles and synaptic mechanisms in the CNS, including synaptic transmission and plasticity.

Study Duration

Not specified

Participants

Not specified

Evidence Level

Review

Key Findings

1
5-HT can either promote or inhibit pain depending on neural circuits, such as spinal pathways. It can also have excitatory or inhibitory functions in the same brain regions, depending on its receptors.
2
The 5-HT system is integrated with pain/anxiety pathways, suggesting roles in regulating pain and injury-related anxiety. 5-HT influences synaptic transmission and plasticity in areas like the ACC and spinal cord.
3
5-HT receptors in the spinal cord can be either pronociceptive or antinociceptive. In the spinal cord, activation of the 5-HT1A, 5-HT1B, 5-HT1D, and 5-HT7 receptors tends to be antinociceptive, whereas the 5-HT2A and 5-HT3 receptors tend to promote nociception

Research Summary

This review discusses the multiple actions of the 5-HT system in both chronic pain and injury-related anxiety, and the synaptic mechanisms behind them. The specific 5-HT receptors would be new promising therapeutic targets for the effective treatment of chronic pain and injury-related anxiety in the future. 5-HT acts with both nociceptive and antinociceptive or even biphasic eﬀects depending on the type of receptor, amount of substance, and anatomical region. In humans, an acute tryptophan depletion (ATD) in the brain can alter pain perception Synaptic modulation mediated by 5-HT is an important mechanism underlying its physiological function. Previous studies have shown that 5-HT can produce both excitatory and inhibitory modulation at spinal glutamatergic synapses, consistent with the biphasic modulatory eﬀects of 5-HT on spinal nociceptive transmission and behavioral reﬂexes

Practical Implications

Therapeutic targets

Specific 5-HT receptors may represent new therapeutic targets for treating chronic pain and injury-related anxiety.

Treatment strategies

Understanding the roles of different 5-HT receptor subtypes in the spinal cord and brain could inform novel treatment strategies for chronic pain.

Synaptic mechanisms

Further research at the synaptic level could provide new insights into treating chronic pain by modulating the 5-HT system's effects on synaptic transmission and plasticity.

Study Limitations

1
The therapeutic mechanisms of drugs like alosetron and fluoxetine are still unclear.
2
More studies are required to precisely clarify the roles of spinal 5-HT receptors in chronic pain.
3
The exploration of 5-HT-mediated synaptic plasticity is still in its initial stages.

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