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Aim: To investigate the role of hypothalamus nociceptin/orphanin FQ (OFQ) and its endogenous receptor, the opioid receptor-likel receptor (ORL1 receptor) in the estrus cycle of female rats. Method: Radioimmunoassay was used to detect the effect of the intracerebroventricular (icv) administration of OFQ and/or the ORL1 receptor antagonist [Nphel]Nociceptin(1-13)NH2 that is, NC13 on luteinizing hormone (LH) levels of estrogen- and progesterone (EBP)-primed, ovariectomized (OVX) rats (EBP-primed OVX rats). RT-PCR, Weste blotting, and immunohis- tochemistry techniques were adopted to observe the changes of OFQ and the ORL1 receptor in the pre-optic area (POA) and the medial basal hypothalamus (MBH) of the estrus cycle of female rat. Results: Pre-ovulatory LH surges in EBP-primed, OVX rats were significantly reduced by icv administration of 20 and 200 nmol OFQ (P<0.05), and the effect of 20 nmol OFQ could be abolished by pretreat-ment with 20 nmol NC13. The OFQ mRNA level in the POA on pro-estrus was lowered markedly compared to diestrus and estrus (P<0.05), while the mRNA and protein levels of the ORL1 receptor showed no significant changes in the POA and MBH across the estrus cycle. Meanwhile, the number of OFQ-immunoreac-tive neurons in the medial POA, ventromedial hypothalamus, and the arcuate nucleus on pro-estrus was significantly decreased compared to diestrus and es-trus (P<0.05). Conclusion: The inhibitory effect of OFQ on the LH surge of EBP-primed, OVX rats and its downregulation in POA and MBH on pro-estrus sug-gests that it might play a negative modulatory role in the estrus cycle.