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Updated: Jun 23, 2026
The Sciatic Nerve Cuffing Model of Neuropathic Pain in Mice
Published on: July 16, 2014
Peripheral-type benzodiazepine receptor antagonist is effective in relieving neuropathic pain in mice
Daisuke Kondo1, Hironao Saegusa, Ritsuko Yabe
1Department of Pharmacology and Neurobiology, Tokyo Medical and Dental University, Japan.
Abstract:
cDNA microarray analysis showed the expression of peripheral-type benzodiazepine receptor (PBR) mRNA is slightly enhanced in the spinal cord of mice with spinal nerve injury (SNL) as compared with sham-operated mice. PBR transports cholesterol to the mitochondria, where cholesterol is converted to pregnenolone. Pregnenolone is then metabolized to progesterone, an activator of progesterone receptor, and further metabolized to produce allopregnanolone and 3alpha,21-dihydroxy-5alpha-pregnan-20-one (3alpha,5alpha-THDOC), positive allosteric modulators and activators of the GABA(A) receptor. In the present study, we first tested whether the enhanced PBR expression is causally related to neuropathic pain, and we found that the PBR antagonist PK11195 is effective in reducing SNL-induced mechanical allodynia and thermal hyperalgesia. Next we tested whether the PK11195-induced antinociception is attributable to reduced neurosteroid synthesis, which may possibly lead to reduced activation of the progesterone receptor and/or GABA(A) receptor. We found that allopregnanolone and 3alpha,5alpha-THDOC are effective in reducing the anti-hyperalgesic effect of PK11195, suggesting a partial contribution of reduced GABA(A)-receptor activation to PK11195-induced antinociception.
Insights
Peripheral-type benzodiazepine receptor (PBR) antagonism alleviates neuropathic pain by reducing neurosteroid synthesis. This suggests PBR plays a key role in spinal nerve injury pain pathways.
Area of Science:
- Neuroscience
- Pharmacology
- Pain Research
Background:
- Peripheral-type benzodiazepine receptor (PBR) expression is upregulated in spinal nerve injury (SNL).
- PBR facilitates cholesterol transport for neurosteroid synthesis, impacting pain modulation.
- Neurosteroids like allopregnanolone modulate GABA(A) receptors, influencing pain perception.
Purpose of the Study:
- To investigate the causal role of enhanced PBR expression in neuropathic pain.
- To determine if PBR antagonism reduces pain via altered neurosteroid synthesis.
- To elucidate the contribution of GABA(A) receptor activation to PBR antagonist effects.
Main Methods:
- cDNA microarray analysis to assess PBR mRNA expression.
- Administration of PBR antagonist PK11195 in a mouse spinal nerve injury model.
- Assessment of mechanical allodynia and thermal hyperalgesia.
- Evaluation of neurosteroid (allopregnanolone, 3alpha,5alpha-THDOC) effects on PK11195-induced antinociception.
Main Results:
- PBR mRNA expression was enhanced in mice with SNL.
- PK11195 significantly reduced SNL-induced mechanical allodynia and thermal hyperalgesia.
- Allopregnanolone and 3alpha,5alpha-THDOC partially reversed the anti-hyperalgesic effect of PK11195.
Conclusions:
- Enhanced PBR expression is causally linked to neuropathic pain.
- PBR antagonism alleviates neuropathic pain, partly through reduced GABA(A) receptor activation.
- Targeting PBR offers a potential therapeutic strategy for neuropathic pain management.
