Analgesic effects of ASP3662, a novel 11β-hydroxysteroid dehydrogenase 1 inhibitor, in rat models of neuropathic and dysfunctional pain

British Journal of Pharmacology, 2018 · DOI: 10.1111/bph.14448 · Published: January 1, 2018

Pharmacology Rheumatology Pain Management

Simple Explanation

Glucocorticoids, stress hormones, can worsen pain. This study investigates ASP3662, a novel 11β-HSD1 inhibitor's effect on neuropathic and dysfunctional pain, since 11β-HSD1 regenerates glucocorticoids in the CNS. ASP3662 was tested on rats with nerve damage, fibromyalgia, and inflammation. Its ability to block the 11β-HSD1 enzyme and its behavior in the body were also examined. The study found that ASP3662 can block the 11β-HSD1 enzyme, can enter the brain, and has long-lasting effects. It reduced pain in rats with nerve damage and fibromyalgia, but not in rats with inflammatory pain.

Study Duration

Not specified

Participants

Sprague-Dawley rats

Evidence Level

Level 1: Animal study

Key Findings

1
ASP3662 effectively inhibits 11β-HSD1 in humans, mice, and rats, demonstrating selectivity over 11β-HSD2 and showing no significant impact on other enzymes, transporters, and receptors.
2
The study's pharmacokinetic analysis reveals that ASP3662 exhibits CNS penetrability and long-lasting pharmacokinetic properties in Sprague-Dawley rats.
3
In rat models, ASP3662 alleviated mechanical allodynia in spinal nerve ligation and streptozotocin-induced diabetic rats, thermal hyperalgesia in chronic constriction nerve injury rats, and restored muscle pressure thresholds in reserpine-induced myalgia rats.

Research Summary

This study investigates the analgesic effects of ASP3662, a novel 11β-HSD1 inhibitor, in rat models of neuropathic and dysfunctional pain. ASP3662 is a potent, selective, and CNS-penetrable inhibitor of 11β-HSD1, demonstrating efficacy in neuropathic pain models (SNL, CCI, STZ-induced diabetic rats) and a fibromyalgia model (RIM rats). The findings suggest that selective inhibition of 11β-HSD1 may be a promising approach for treating neuropathic and dysfunctional pain, such as that observed in fibromyalgia.

Practical Implications

Drug development

ASP3662 and similar 11β-HSD1 inhibitors show promise as potential treatments for neuropathic and dysfunctional pain conditions like fibromyalgia.

Targeted therapy

Selective 11β-HSD1 inhibition could offer a targeted approach for managing chronic pain, potentially benefiting patients who do not respond to existing treatments.

Further research

Further studies are needed to elucidate the detailed antinociceptive mechanism of action of 11β-HSD1 inhibitors and to monitor its effect on the HPA axis.

Study Limitations

1
The study is limited to animal models, and the results may not directly translate to human clinical outcomes.
2
The study did not fully elucidate the mechanism of action of ASP3662.
3
The long-term effects of 11β-HSD1 inhibition on the HPA axis require further investigation.

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