Activational action of testosterone on androgen receptors protects males preventing temporomandibular joint pain.

BACKGROUND: Testosterone protects male rats from Temporomandibular Joint (TMJ) pain. This study investigated whether this protective effect is mediated by an organizational action of testosterone during nervous system development, by central estrogen and androgen receptors and by the 5α-reduced metabolite of testosterone, dihydrotestosterone. METHODS: A pharmacological approach was used to assess the ability of the androgen receptor antagonist flutamide, the estrogen receptor antagonist ICI 182 780 and the 5-α reductase inhibitor dutasteride to block the protective effect of testosterone, evaluated through the behavioral response induced by a TMJ injection of 0.5% formalin. Flutamide and ICI 182 780 were injected into the medullary subarachnoid space, and dutasteride and testosterone were systemically administered. RESULTS: The TMJ injection of 0.5% formalin induced a significant nociceptive behavioral response in gonadectomized male and naïve female, but not in sham gonadectomized male rats, confirming that endogenous testosterone prevents TMJ nociception in males. Testosterone administration prevented formalin-induced TMJ nociception in males gonadectomized either in the neonatal (at the day of birth) or adult period and in naïve female rats, suggesting that the protective effect of testosterone on TMJ nociception does not depend on its organizational actions during critical periods of development. The administration of flutamide and dutasteride but not of ICI 182 780 blocked the protective effect of testosterone. CONCLUSIONS: We conclude that the protective effect of testosterone on TMJ nociception depends on activational actions of dihydrotestosterone on androgen receptors rather than on organizational androgenic actions during central nervous system development or estrogenic actions.

Effect of gonadal steroid hormones on formalin-induced temporomandibular joint inflammation.

We have recently demonstrated that gonadal steroid hormones decrease formalin-induced temporomandibular joint nociception in rats. Given that the attenuation of inflammation is a potential mechanism underlying this antinociceptive effect, we evaluated the effect of gonadal steroid hormones on formalin-induced temporomandibular joint inflammation. Plasma extravasation, a major sign of acute inflammation, and neutrophil migration, an important event related to tissue injury, were evaluated. Formalin induced significantly lower temporomandibular joint plasma extravasation and neutrophil migration in proestrus females than in males and in diestrus females. Since estradiol serum level is high in proestrus females and low in diestrus females and in males, these findings suggest that the high physiological level of estradiol decreases temporomandibular joint inflammation. Estradiol but not progesterone administration in ovariectomized females significantly decreased formalin-induced plasma extravasation and neutrophil migration, an effect that was blocked by the estrogen receptor antagonist ICI 182780. Plasma extravasation and neutrophil migration were not affected by orchiectomy, but testosterone or estradiol administration in orchidectomized males significantly decreased them. The androgen receptor antagonist flutamide blocked the anti-inflammatory effect of testosterone while ICI 182780 blocked that of estradiol in males. Previous intravenous administration of a nonspecific selectin inhibitor significantly decreased formalin-induced temporomandibular joint nociception and neutrophil migration in males, revealing a potent and positive correlation between temporomandibular joint nociception and inflammation. Taken together, these findings demonstrate a pronounced anti-inflammatory effect of estradiol and testosterone in the temporomandibular joint region and suggest that this effect may mediate, at least in part, the antinociceptive effect of these hormones.

Peripheral estradiol induces temporomandibular joint antinociception in rats by activating the nitric oxide/cyclic guanosine monophosphate signaling pathway.

Recently, we have reported that high physiological estradiol level during the proestrus phase of the estrous cycle or systemic estradiol administration in ovariectomized rats decreases formalin-induced temporomandibular joint nociception. However, the mechanisms underlying the antinociceptive effect of estradiol are presently unknown. In this study, we used the temporomandibular joint formalin model in rats to investigate whether estradiol decreases nociception by a peripheral non-genomic mechanism, and if so, whether this mechanism is mediated by the activation of the nitric oxide-cyclic guanosine monophosphate signaling pathway and of opioid receptors. The administration of estradiol into the ipsilateral, but not into the contralateral temporomandibular joint significantly reduced formalin-induced temporomandibular joint nociception in ovariectomized and diestrus but not in proestrus females. However, the administration of the estrogen receptor antagonist ICI 182780 into the ipsilateral, but not into the contralateral temporomandibular joint blocked the antinociceptive effect of serum estradiol in proestrus females, suggesting that the physiological effect of estradiol in nociception is mediated, at least in part, by a peripheral mechanism. The administration of estradiol into the ipisilateral temporomandibular joint did not affect formalin-induced nociception in male rats. The antinociceptive effect of temporomandibular joint estradiol administration in ovariectomized and diestrus females was mimicked by estradiol conjugated with bovine serum albumin, which does not diffuse through the plasma membrane, and was blocked by the estrogen receptor antagonist ICI 182780. The administration of the nitric oxide synthase inhibitor (nitro-l-arginine) or of a guanylate cyclase inhibitor (1H-(1,2,4)-oxadiasolo (4,2-a) quinoxalin-1-one) into the ipsilateral, but not into the contralateral temporomandibular joint blocked the antinociceptive effect of estradiol and of estradiol conjugated with bovine serum albumin, while the opioid receptor antagonist naloxone had no effect. These findings suggest that estradiol decreases temporomandibular joint nociception in female rats through a peripheral non-genomic activation of the nitric oxide-cyclic guanosine monophosphate signaling pathway.