Spinal neuropeptide Y Y1 receptor-expressing neurons are a pharmacotherapeutic target for the alleviation of neuropathic pain

PNAS, 2022 · DOI: https://doi.org/10.1073/pnas.2204515119 · Published: November 7, 2022

Simple Explanation

This study identifies a potential drug target for neuropathic pain: neuropeptide Y (NPY) Y1 receptor-expressing interneurons (Y1-INs) in the spinal cord. Researchers found that nerve injury increases the excitability of these neurons, leading to pain. Activating Y1-INs in uninjured mice caused signs of spontaneous and allodynic pain. Conversely, inhibiting these neurons reduced nerve injury-induced allodynia. This suggests that Y1-INs play a crucial role in neuropathic pain. The study also found that a Y1-selective agonist, when administered intrathecally, reduced allodynia. Conditional deletion of Npy1r in dorsal horn neurons, but not peripheral afferent neurons, prevented the anti-hyperalgesic effects of the intrathecal Y1 agonist.

Study Duration

Not specified

Participants

Mice

Evidence Level

Not specified

Key Findings

1
Spared nerve injury (SNI) enhances the excitability of Y1-INs and elicits allodynia and affective pain.
2
Chemogenetic or optogenetic activation of Y1-INs in uninjured mice elicits behavioral signs of spontaneous, allodynic, and affective pain.
3
SNI-induced allodynia was reduced by chemogenetic inhibition of Y1-INs, or intrathecal administration of a Y1-selective agonist.

Research Summary

This study investigates the role of spinal neuropeptide Y Y1 receptor-expressing neurons (Y1-INs) in neuropathic pain. The researchers found that nerve injury increases the excitability of Y1-INs, leading to allodynia and affective pain. Chemogenetic and optogenetic activation of Y1-INs in uninjured mice induced pain-like behaviors, while inhibiting these neurons reduced SNI-induced allodynia. These findings indicate that Y1-INs are both necessary and sufficient for the behavioral symptoms of neuropathic pain. Intrathecal administration of a Y1-selective agonist reduced SNI-induced allodynia, and conditional deletion of Npy1r in dorsal horn neurons prevented the anti-hyperalgesic effects of the agonist. This suggests that spinal Y1-INs are a promising target for pharmacotherapeutic development of Y1 agonists.

Practical Implications

Therapeutic Target

Spinal Y1-INs represent a promising therapeutic target for the development of Y1 agonists to treat neuropathic pain.

Analgesic Development

The findings support the development of spinally directed Y1 receptor agonists as a therapeutic strategy.

Clinical Translation

Spinally administered Y1 agonists remain efficacious in chronic neuropathic pain states long-term, a critical result for future clinical translation.

Study Limitations

1
The study primarily used animal models (mice), and further research is needed to confirm these findings in humans.
2
The specific molecular mechanisms underlying the increased efficiency of coupling between NPY Y1 receptors and G proteins after nerve injury are not fully defined.
3
One limitation of our recordings is that we utilized a nonsurgical (anesthesia) control and therefore we cannot exclude the possibility that some excitability changes associated with the nerve injury surgery may be due to skin or muscle damage.

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