Phase-speciﬁc differential regulation of mechanical allodynia in a murine model of neuropathic pain by progesterone

Frontiers in Pharmacology, 2023 · DOI: 10.3389/fphar.2023.1253901 · Published: December 11, 2023

Simple Explanation

Progesterone, a neurosteroid, can have neuroprotective effects, but clinical studies show conflicting results. This study investigates how progesterone affects neuropathic pain in mice after chronic constriction injury (CCI) of the sciatic nerve. The study found that progesterone's effects on pain depend on the phase of pain (induction vs. maintenance) and involve specific enzymes (cytochrome P450c17 and 5α-reductase) in the spinal cord. During the induction phase of chronic pain, progesterone can worsen pain by stimulating spinal astrocytes via P450c17 activation. Conversely, during the maintenance phase, it can alleviate pain by suppressing astrocyte activation via 5α-reductase.

Study Duration

Not specified

Participants

Male Crl:CD1(ICR) mice that were 5 weeks old (23 ± 2 g)

Evidence Level

Original Research

Key Findings

1
Intrathecal progesterone administration during the induction phase of chronic pain enhanced mechanical allodynia development and spinal GFAP expression, an effect inhibited by a P450c17 inhibitor.
2
In contrast, intrathecal progesterone administration during the maintenance phase of chronic pain decreased acquired pain and elevated GFAP expression; this inhibition was restored by a 5α-reductase inhibitor.
3
Sciatic nerve injury increased phospho-serine levels of P450c17 in the spinal cord on day 1 after CCI operation, but not on day 17, suggesting phase-specific enzyme activity.

Research Summary

This study investigates the phase-specific effects of progesterone on neuropathic pain in mice with sciatic nerve injury, focusing on the roles of P450c17 and 5α-reductase. The research reveals that progesterone enhances mechanical allodynia during the induction phase via P450c17 activation but reduces it during the maintenance phase through 5α-reductase activation. These findings suggest that progesterone's impact on neuropathic pain is dependent on the stage of the condition and the activity of specific metabolic enzymes in the spinal cord.

Practical Implications

Therapeutic Targeting

Consider phase-specific treatments; P450c17 inhibitors may be beneficial during the induction phase, while 5α-reductase may be more effective during the maintenance phase.

Drug Development

Develop progesterone-based therapies that selectively target specific enzymes (P450c17 or 5α-reductase) to maximize analgesic effects and minimize adverse outcomes.

Personalized Medicine

Assess individual patient's pain phase and metabolic enzyme activity to tailor progesterone treatment for optimal efficacy in neuropathic pain management.

Study Limitations

1
Study conducted only on male mice
2
Focus on mechanical allodynia; other pain types not examined
3
Specific signaling pathways and receptors involved in progesterone's actions require further investigation

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