Estrogen-dependent facilitation on spinal reflex potentiation involves the Cdk5/ERK1/2/NR2B cascade in anesthetized rats

Hsien Yu Peng, Gin Den Chen, Kwong Chung Tung, Ya Wen Chien, Cheng Yuan Lai, Ming Chun Hsieh, Chun Hsien Chiu, Cheng Hung Lai, Shin Da Lee, Tzer Bin Lin

Research output: Contribution to journalArticlepeer-review

29 Citations (Scopus)


Cyclin-dependent kinase-5 (Cdk5), a proline-directed serine/threonine kinase, may alter pain-related neuronal plasticity by regulating extracellular signal-related kinase-1/2 (ERK1/2) activation. This study investigated whether Cdk5-dependent ERK activation underlies the estrogen-elicited facilitation on the repetitive stimulation-induced spinal reflex potentiaton (SRP) that is presumed to be involved in postinflammatory/neuropathic hyperalgesia and allodynia. Reflex activity of the external urethra sphincter electromyogram evoked by pelvic afferent nerve test stimulation (TS; 1 stimulation/30 s for 10 min) and repetitive stimulation (RS; 1 stimulation/1 s for 10 min) was recorded in anesthetized rats. TS evoked a baseline reflex activity, whereas RS produced SRP. Intrathecal (it) β-estradiol facilitated the repetitive stimulation-induced SRP that was reversed by pretreatment with the estrogen receptor anatogonist ICI 182,780 (10 nM, 10 μl it), Cdk5 inhibitor roscovitine (100 nM, 10 μl it), ERK inhibitor (U-0126; 100 μM, 10 μl it) and N-methyl-D-aspartate (NMDA) NR2B subunit antagonist (Co-101244; 100 nM, 10 μl it). Moreover, ERα (propylpyrazoletriol; 100 nM, 10 μl it) and ERβ (diarylpropionitrile; 100 μM, 10 μl it) agonists both facilitated the SRP, similar to results with a β-estradiol injection. In association with the facilitated RS-induced SRP, an intrathecal β-estradiol injection elicited ERK1/2 and NR2B subunit phosphorylation that were both reversed by intrathecal roscovitine and U-0126. These results indicated that the Cdk/ERK cascade, which is activated by ERα and ERβ, may subsequently phosphorylate the NR2B subunit to develop NMDA-dependent postinflammatory hyperalgesia and allodynia to maintain the protective mechanisms of the body.

Original languageEnglish
Pages (from-to)E416-E426
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Issue number2
Publication statusPublished - Aug 2009
Externally publishedYes


  • Cyclin-dependent kinase-5
  • Estradiol
  • Extracellular signal-related kinase
  • Hyperalgesia
  • NR2B
  • Pelvic pain
  • Spinal reflex potentiaton

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Physiology (medical)


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