We recently reported that exogenously applied orphanin FQ, the endogenous ligand for opioid receptor-like 1 (ORL(1)) receptor, produces sex-specific modulation of trigeminal nociception, and that estrogen contributes to these sex-related differences. Estrogen could produce these sex-related differences by altering the expression of the ORL(1)-receptor gene in the trigeminal nucleus caudalis. Utilizing in situ hybridization, we compared levels of ORL(1) receptor mRNA and investigated its colocalization with estrogen receptor mRNA in trigeminal neurons. Our results showed that in male rats, ORL(1) receptor mRNA is abundantly expressed in the rostral part of the trigeminal nucleus caudalis, and at the junction of caudalis and interpolaris (Vc/Vi). In comparison with males, levels of ORL(1) receptor mRNA were not significantly different in proestrus females, but were significantly higher in the rostral trigeminal nucleus caudalis and at the junction of Vc/Vi of diestrus females. In addition, ovariectomy raised the levels in the rostral trigeminal nucleus caudalis, and at the junction of Vc/Vi. Levels were reduced to proestrus levels in these regions following estradiol replacement. Our results also showed that ORL(1) receptor mRNA is present in majority of estrogen receptor (alpha and/or beta) mRNA-containing neurons. We conclude that there are sex-related differences in the ORL(1)-receptor gene expression in the trigeminal nucleus caudalis, which appear to be determined in part by estrogen levels.