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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.

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The authors have recently demonstrated that the high serum estradiol level during the proestrus phase of the estrous cycle and that the administration of estradiol or progesterone in ovariectomized female and of testosterone in orchiectomized male rats significantly decrease formalin-induced temporomandibular joint (TMJ) nociception. In this study, the authors investigate the contribution of endogenous opioids to this antinociceptive effect of gonadal hormones in the TMJ formalin test. The opioid receptor antagonist naloxone was administrated either in the surrounding of the trigeminal sensory complex or in the TMJ region. The antinociceptive effect induced by endogenous estradiol in proestrus females and by exogenous estradiol in ovariectomized females was blocked by the administration of naloxone in the surrounding of the trigeminal sensory complex, but not in the TMJ region. The antinociceptive effect induced by the administration of progesterone in ovariectomized females and of testosterone in orchiectomized males was blocked by the administration of naloxone either in the surrounding of the trigeminal sensory complex or in the TMJ region. The authors conclude that central and peripheral opioid mechanisms mediate the antinociceptive effect of progesterone and testosterone, and central opioid mechanisms mediate the antinociceptive effect of estradiol. These findings suggest that the enhanced pain perception during low gonadal hormone periods in women and animals may be mediated by a decrease in endogenous opioid activity. This suggestion helps explain the higher severity of some pain conditions, such as temporomandibular dysfunctions in women than in men, that have no hormonal fluctuations.

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Temporomandibular joint pain-related conditions are generally characterized by local inflammation; however, little studies have focused on the role of gonadal hormones in the expression of inflammatory mediators, such as cytokines. Therefore, we asked whether gonadal steroid hormones affect formalin-induced cytokines expression in the rat temporomcandibular joint. The expression of tumor necrosis factor alpha (TNF-α), interleukin (IL)-1β, and cytokine-induced neutrophil chemoattractant (CINC)-1 was significantly higher in males than in diestrus and proestrus females and was decreased by orchiectomy and restored by testosterone replacement. The expression of IL-6 was significantly higher in diestrus and proestrus females than in males, and was decreased by ovariectomy and restored by estradiol or progesterone administration. We conclude that testosterone increases the expression of TNF-α, IL-1β and CINC-1, and estradiol and progesterone increase the expression of IL-6. New clinical approaches based on inhibition of pro-inflammatory mediators are starting to supplant traditional immunosuppressive therapies and gonadal hormones may influence their effectiveness or clinical dosage.

In an attempt to decrease central side effects associated with the use of opioids, some strategies have been developed by targeting peripheral opioid receptors. In this context, kappa receptors are of major interest, since, in contrast to other opioid receptors, their activation is not associated with potent peripheral side effects. We have recently demonstrated that local activation of kappa opioid receptors significantly decreases formalin-induced temporomandibular joint nociception; however, whether it also decreases temporomandibular joint inflammation is not known. To address this issue, we evaluated if a specific kappa opioid receptor agonist, U50,488 (trans-(1S,2S)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl] benzeneacetamide hydrochloride hydrate), administered into the temporomandibular joint decreases formalin-induced plasma extravasation and neutrophil migration. Ipsilateral, but not contralateral, administration of U50,488 into the temporomandibular joint blocked formalin-induced plasma extravasation and neutrophil migration in a dose-dependent manner. This anti-inflammatory effect was reversed by the ipsilateral, but not contralateral, administration of the kappa opioid receptor antagonist nor-BNI (nor-binaltorphimine dihydrochloride). This study demonstrates that local activation of kappa opioid receptors decreases two important parameters of temporomandibular joint inflammation, that is, plasma extravasation and neutrophil migration, in a dose-dependent and antagonist-reversible manner. This anti-inflammatory effect taken together with the potent antinociceptive effect, suggests that drugs targeting peripheral kappa opioid receptors are promising for the treatment of inflammatory temporomandibular joint pain and probably, other articular pain conditions with an inflammatory basis.

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