NMDA receptor blockade reduces temporomandibular joint-evoked activity of trigeminal subnucleus caudalis neurons in an estrogen-dependent manner

Abstract

Estrogen status is a risk factor in painful temporomandibular disorders (TMJD). Previously we reported that estradiol (E2) enhanced nociceptive processing of TMJ input by neurons in superficial laminae at the spinomedullary (Vc/C1-2) region; however, the mechanisms for this enhancement are not known. The present study determined if ionotropic glutamate receptors contribute to TMJ nociceptive processing in an E2-dependent manner. Ovariectomized (OvX) female rats were treated with high E2 (HE2) or low dose E2 (LE2) for 2 days and neural activity was recorded in laminae I-II at the Vc/C1-2 region. TMJ-responsive units were activated by adenosine triphosphate (ATP) injections into the joint space. ATP-evoked unit responses in HE2 rats were reduced significantly by topical application of the N-methyl-D-aspartate receptor antagonist, D(−) -2-amino-5-phosphonopentanoic acid (AP5) in a dose-related manner, while units from LE2 were not affected. Application of the non-NMDA receptor antagonist, 6,7-dinitroquinoxaline-2,3-dione (DNQX), inhibited the ATP-evoked responses in both groups. Spontaneous activity of TMJ units was not influenced by AP5, whereas it was reduced by DNQX similarly in both groups. The high threshold convergent cutaneous receptive field area of TMJ units was not changed by AP5, whereas DNQX caused a significant reduction in both groups. These results suggest that NMDA-dependent mechanisms contribute to the enhanced ATP-evoked responses of TMJ units in superficial laminae at the Vc/C1-2 region under high E2 conditions, while non-NMDA-dependent mechanisms modify the encoding properties of TMJ units independent of E2 status.

The Influence of Menstrual Phases on Pain Modulation in Healthy Women

“…1,24 Another possible mechanism is interaction with N-methyl-D-aspartate (NMDA) receptors in the spinal cord/brainstem, because it has been shown in rats that NMDA receptor antagonists reduced the activity of neurons in laminae I and II of the trigeminal subnucleus caudalis in an estrogen-dependent manner. 38 To summarize, there are many possible mechanisms by which sex hormones may modulate pain, and the net effect (enhancement or inhibition) may be due to the balance between them and in receptor expression between spinal and more central central nervous system regions.…”

GABAergic influence on temporomandibular joint-responsive spinomedullary neurons depends on estrogen status

“…Previously we determined that the response properties of TMJ neurons in superficial laminae varied significantly over different stages of the estrous cycle in intact female rats (Okamoto et al 2003), while exogenous E2 treatment increased the TMJ-evoked responses of neurons in superficial but not in deeper laminae in ovariectomized female rats (Tashiro et al 2007; Okamoto et al 2013). Although estrogen status markedly affected the response of TMJ-responsive neurons to NMDA receptor antagonism (Tashiro et al, 2009a) and inhibition of MAP kinase activity consistent with central sensitization (Tashiro et al, 2009b), little is known about estrogen status, disinhibition and GABAergic function in TMJ nociception. GABAergic neurons are found throughout the trigeminal brainstem sensory complex and are densely distributed in superficial laminae of Vc (Ginestal and Matute, 1993; Polgar and Antal, 1995; Avendano et al, 2005).…”

Local group I mGluR antagonists reduce TMJ-evoked activity of trigeminal subnucleus caudalis neurons in female rats

“…Data were collected without prior knowledge of E2 treatment. Although plasma E2 levels were not routinely measured, we reported previously, using a similar dosing regimen, that low and high E2-treated OvX female rats had <20 and 50-100 pg/ml E2 in the plasma, respectively, and displayed vaginal smear cytology equivalent to that seen here (Tashiro et al, 2009a).…”

“…By contrast, PD98059 caused a marked and similar reduction in ATP-evoked neural activity after TMJ inflammation independent of E2 treatment suggesting a shared pathway (Tashiro et al, 2009b). Similarly, local application of AP5, a selective NMDA receptor antagonist, greatly reduced the ATP-evoked responses of superficial laminae neurons in HE female rats, while no effect was seen on TMJ units from LE rats (Tashiro et al, 2009a). Two possible explanations for why E2 status did not have greater differential effects on mGluR modulation TMJ nociception, while significant effects were seen on downstream signaling pathways mediated by group I mGluRs.…”