Repeated nociceptive stimulation induces different behavioral and neuronal responses in intact and gonadectomized female rats

Tissue damage induces acute pain but also long-term central modifications that can affect the behavioral and neuronal responses to a second painful stimulus. To study the effects of female gonadal hormones on the responses to repetition of a nociceptive stimulus, we subjected adult female rats to the formalin test. Three weeks after gonadectomy (GDX) or sham-surgery (INT), animals were randomly divided into groups to be left in the home cage as controls (HC) or to be exposed to Sham (S) or Formalin (F) stimuli (s.c. formalin injection, 50 μl, 5%, in the dorsal hind paw) in the subsequent 2 weeks (Trial 1; Trial 2). The resulting groups were: INT or GDX SS (Sham–Sham), SF (Sham–Form) and FF (Form–Form). During Trial 1, licking duration was longer in the INT-FF group than in GDX-FF; during Trial 2, there was no difference between the two groups due to the decrease in INT-FF alone. c-Fos expression, determined in the arcuate nucleus of the hypothalamus in the same animals 1 week after the last formalin test, was higher in GDX than INT animals; moreover, while in INT rats, c-Fos was higher in the formalin-injected animals (SF and FF) than in HC, in GDX, it did not differ among groups. These results show that female gonadal hormones affect the behavioral and neuronal responses to repeated nociceptive stimulation, indicating a possible role of ovarian hormones in determining sex differences in pain.