The Utility of Peripherally Restricted Kappa-Opioid Receptor Agonists for Inhibiting Below-Level Pain after Spinal Cord Injury in Mice

Neuroscience, 2023 · DOI: 10.1016/j.neuroscience.2023.07.017 · Published: September 1, 2023

Spinal Cord Injury Neurology Pain Management

Simple Explanation

Spinal cord injuries (SCI) can cause chronic pain that is difficult to treat. This study investigates the potential of drugs targeting opioid receptors outside the central nervous system (CNS) to manage SCI pain, aiming to reduce central side effects. The study focuses on asimadoline and ICI-204448, believed to be peripherally restricted KOR agonists. The goal was to determine if these drugs could alleviate pain hypersensitivity in mice with spinal cord injuries. The research also explored the peripheral neuronal mechanisms through which ICI-204448 might inhibit pain, using in vivo calcium imaging of dorsal root ganglion (DRG) in mice after SCI.

Study Duration

6 Weeks

Participants

C57BL/6J mice, Pirt-GCaMP6s+/‒ mice

Evidence Level

Not specified

Key Findings

1
Systemic administration of ICI-204448 and asimadoline reduced below-level pain hypersensitivity in SCI mice. However, high-dose asimadoline adversely affected the exploratory performance of SCI mice and caused aversion.
2
High-dose ICI-204448 did not impair exploration and remained effective in reducing both mechanical and heat hypersensitivities after SCI.
3
ICI-204448 attenuated the increased fluorescence intensity of lumbar DRG neurons activated by a noxious pinch stimulation in SCI mice, suggesting reduced neuronal excitability.

Research Summary

This study examined whether peripherally restricted KOR agonists can attenuate pain hypersensitivity in mice subjected to a contusive T10 SCI. Systemic administration of ICI-204448 achieved SCI pain inhibition at doses that did not induce notable side effects and attenuated DRG neuronal excitability which may partly contribute to its pain inhibition. These findings suggest that peripherally restricted KOR agonists may be useful for treating SCI pain, but the therapeutic window must be carefully examined.

Practical Implications

Potential for SCI Pain Treatment

Peripherally restricted KOR agonists may offer a new approach to treating SCI pain by reducing pain signals without the central side effects associated with traditional opioids.

Targeted Pain Relief

ICI-204448's ability to reduce DRG neuron excitability suggests a specific mechanism for alleviating mechanical pain hypersensitivity after SCI.

Careful Dose Consideration

The study highlights the importance of carefully examining the therapeutic window of KOR agonists to avoid potential CNS penetration and adverse effects.

Study Limitations

1
The study was conducted on mice, and results may not directly translate to humans.
2
The study focused on below-level pain and may not address other types of SCI pain.
3
Calcium transients are not as sensitive and fast as action potentials in reflecting changes in neuronal activities

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