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

doi:10.1152/ajpendo.00129.2009

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

Hsien-Yu Peng,¹^,2^,* Gin-Den Chen,³ Kwong-Chung Tung,² Ya-Wen Chien,⁴ Cheng-Yuan Lai,¹^,2 Ming-Chun Hsieh,¹ Chun-Hsien Chiu,² Cheng-Hung Lai,² Shin-Da Lee,⁵^,6^,* and Tzer-Bin Lin¹^,7^,8

¹Department of Physiology, ⁴Graduate Institute of Medicine, College of Medicine, ³Department of Obstetrics and Gynecology, Chung-Shan Medical University Hospital, Chung-Shan Medical University; ²Department of Veterinary Medicine, College of Veterinary Medicine, National Chung-Hsing University; ⁵Department of Physical Therapy, Graduate Institute of Rehabilitation Science, China Medical University; ⁶Department of Healthcare Administration, Asia University, Taichung; ⁷Medical Department, Saint Paul's Hospital, Taoyuan; and ⁸Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei, Taiwan

Submitted 27 February 2009 ; accepted in final form 28 May 2009

Cyclin-dependent kinase-5 (Cdk5), a proline-directed serine/threoninekinase, may alter pain-related neuronal plasticity by regulatingextracellular signal-related kinase-1/2 (ERK1/2) activation.This study investigated whether Cdk5-dependent ERK activationunderlies the estrogen-elicited facilitation on the repetitivestimulation-induced spinal reflex potentiaton (SRP) that ispresumed to be involved in postinflammatory/neuropathic hyperalgesiaand allodynia. Reflex activity of the external urethra sphincterelectromyogram 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 anesthetizedrats. TS evoked a baseline reflex activity, whereas RS producedSRP. Intrathecal (it) β-estradiol facilitated the repetitivestimulation-induced SRP that was reversed by pretreatment withthe estrogen receptor anatogonist ICI 182,780 (10 nM, 10 µlit), Cdk5 inhibitor roscovitine (100 nM, 10 µl it), ERKinhibitor (U-0126; 100 µM, 10 µl it) and N-methyl-D-aspartate(NMDA) NR2B subunit antagonist (Co-101244; 100 nM, 10 µlit). Moreover, ER ${alpha}$ (propylpyrazoletriol; 100 nM, 10 µlit) and ERβ (diarylpropionitrile; 100 µM, 10 µlit) agonists both facilitated the SRP, similar to results witha β-estradiol injection. In association with the facilitatedRS-induced SRP, an intrathecal β-estradiol injection elicitedERK1/2 and NR2B subunit phosphorylation that were both reversedby intrathecal roscovitine and U-0126. These results indicatedthat the Cdk/ERK cascade, which is activated by ER ${alpha}$ and ERβ,may subsequently phosphorylate the NR2B subunit to develop NMDA-dependentpostinflammatory hyperalgesia and allodynia to maintain theprotective mechanisms of the body.

estradiol; cyclin-dependent kinase-5; NR2B; extracellular signal-related kinase; pelvic pain; spinal reflex potentiaton; hyperalgesia

Address for reprint requests and other correspondence: T.-B. Lin, Dept. of Physiology, College of Medicine, Chung-Shan Medical University, No. 110, Chang-Kuo North Rd. 1st Section, Taichung, Taiwan 40201 (E-mail: tblin{at}csmu.edu.tw)