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Objective Estrogen plays a key role in pain perception.But the effect is inconsistent and the mechanism is still unclear.This study used OVX rat model to measure the pain behavior in basal, inflammatory and neuropathic pain (CCI model) and to study the possible mechanism.Methods We used the behavioral test: von Frey test (hindlimbs), Hargreavestest (hindlimbs), tail flick test (proximal and distal tail) and formalin test in different groups to measure the nociceptive responses.The location of estrogen receptors (ERs) were identified by irnmunofluorescence staining.And Western blot was used to measure the protein level of ER and Akt.Results (1) Significant allodynia and hyperalgesia appeared 5 weeks post-OVX surgery and could be attenuated by long term 17β-estradiol (E2) replacement (s.c., 1 week).But CCI did not produce further decrease of mechanical pain threshotd in OVX rats.This indicated the relatively lower level of estrogen might inhibit the allodynia accompanied by neuropathic pain.(2) Double immunofluorescence showed co-localization of ERα and ERβ with NeuN (neuronal marker) but not with GFAP (astrocyte marker) and OX42 (microglia marker) in spinal.(3) ERα and Akt were up-regulated in 5 weeks after OVX surgery and could be restored after E2 administration.(4) The formalin nociceptor responses were decreased after intrathecal injection of PI3K inhibitor (wortmannin).Conclusion ERain spinal neuron may play an important role in the induction of hyperalgesia and allodynia in OVX rats through PI3K/Akt.