Chronic 17β-estradiol pretreatment has pronociceptive effect on behavioral and morphological changes induced by orofacial formalin in ovariectomized rats

BACKGROUND: The prevalence of craniofacial pain disorders show sexual dimorphism with generally more common appearance in women suggesting the influence of estradiol, but the exact cause remains unknown. The common point in the pathogenesis of these disorders is the activation of trigeminal system. One of the animal experimental models of trigeminal activation is the orofacial formalin test, in which we investigated the effect of chronic 17β-estradiol pretreatment on the trigeminal pain-related behavior and activation of trigeminal second-order neurons at the level of spinal trigeminal nucleus pars caudalis (TNC). METHODS: Female Sprague Dawley rats were ovariectomized and silicone capsules were implanted subcutaneously containing cholesterol in the OVX group and 17β-estradiol and cholesterol in 1:1 ratio in the OVX+E(2) group. We determined 17β-estradiol levels in serum after the implantation of capsules. Three weeks after operation, 50 µL of physiological saline or 1.5% of formalin solution was injected subcutaneously into the right whisker pad of rats. The time spent on rubbing directed to the injected area and c-Fos immunoreactivity in TNC was measured as the formalin-induced pain-related behavior, and as the marker of pain-related neuronal activation, respectively. RESULTS: The chronic 17β-estradiol pretreatment mimics the plasma levels of estrogen occurring in the proestrus phase and significantly increased the formalin-induced pain-related behavior and neuronal activation in TNC. CONCLUSION: Our results demonstrate that the chronic 17β-estradiol treatment has strong pronociceptive effect on orofacial formalin-induced inflammatory pain suggesting modulatory action of estradiol on head pain through estrogen receptors, which are present in the trigeminal system.