Cyclin dependent kinase-5 (Cdk5), a proline-directed serine/theonine kinase, may alter the pain-related neuronal plasticity by regulating extracellular signal-related kinase 1/2 (ERK 1/2) activation. This study investigated whether Cdk5-dependent ERK activation underlies in the estrogen-elicited facilitation on the repetitive stimulation-induced spinal reflex potentiaiton (SRP) that is presumed to be involved in the post-inflammatory/neuropathic hyperalgesia and allodynia. Reflex activity of the external urethra sphincter electromyogram evoked by pelvic afferent nerve test stimulation (TS, 1 stimulation/30 sec for 10 min) and repetitive stimulation (RS, 1 stimulation/1 sec for 10 min) was recorded in anesthetized rats. TS evoked a baseline reflex activity, whereas RS produced SRP. Intrathecal -estrodiol facilitated the repetitive stimulation-induced SRP that was reversed by pretreatment of the estrogen receptor anatogonist (ICI 182,780, 10 nM, 10 uL, i.t.), Cdk5 inhibitor (roscovitine, 100 nM, 10 uL, i.t.), ERK inhibitor (U0126, 100 uM, 10 uL, i.t.) and NMDA NR2B subunit antagonist (Co-101244, 100 nM, 10 uL, i.t.). Moreover, ER(PPT, 100 nM, 10 uL, i.t.) and ER (DPN, 100 uM, 10 uL, i.t.) agonists both facilitated the SRP similar to that done by -estrodiol injection. In associated with facilitated the RS-induced SRP, intrathecal-estrodiol injection elicited ERK 1/2 and NR2B subunit phosphorylation that was both reversed by intrathecal roscovitine and U0126. All these result indicated the Cdk/ERK cascade, which was activated by the ER and ER receptors, may subsequently phosphorylate the NR2B subunit to develop NMDA-dependent post-inflammatory hypergesia and allodynia for maintaining the protect mechanism in body.