Mechanism for sex difference in pain responses (1) Mapping of and time course of the exression of phosphorylated CREB induced by formalin

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Formalin injection induces two phases of nociceptive responses separated by interphase, a brief quiescent period. This pattern was similar in both sexes, but there was a prominent increase in nociceptive response during interphase in female rats. Next, the expression of phosphorylated CREB (pCREB) was immunohistochemically examined during various times after formalin injection. We found that the number of pCREB-immunoreactive cells (pCREB cells) in the bilateral dorsolateral divisions of the bed nucleus of the stria terminalis (BSTLD) was significantly increased by formalin injection in females, but not in males. These changes were observed selectively 5-10 min after formalin injection, a period corresponding to behavioral interphase, and were specific to formalin injection. These data indicate that the CREB in the BSTLD is phosphorylated in a female-specific manner in association with the sex difference in the formalin test. We next examined the effects of castration and testosterone or 17β-estradiol replacement Behavioral data indicated the involvement of estrogen in interphase. In parallel with the behavioral data, there were no changes in the number of pCREB cells in the BSTLD of orchidectomized rats 5-10 min (interphase) after formalin injection irrespective of steroid replacement. In ovariectomized rats, however, the number of pCREB cells in the testosterone or estrogen replaced groups injected with formalin was significantly greater than in the saline injected rats. Furthermore, formalin injection failed to increase the pCREB expression in ovariectomized rats without steroid replacement. These results indicate that the changes in both behavioral and pCREB responses observed during interphase are gonadal steroid-dependent in female rats.