17- -Estradiol Enhanced Allodynia of Inflammatory Temporomandibular Joint through Upregulation of Hippocampal TRPV1 in Ovariectomized Rats

Abstract

Temporomandibular disorders (TMDs) predominantly affect reproductive female patients, with pain the most frequent complaint. Although estrogens are believed to play important roles in TMD pain, the mechanism underlying modulation of TMD pain by estrogens remains largely unknown. Accumulating evidence implies that the hippocampus is involved in sexual dimorphism of pain sensitivity. In this study, we investigated the hippocampal TRPV1 (transient receptor potential vanilloid 1) expression in ovariectomized rats that received 17-␤-estradiol substitution and found that 17-␤-estradiol enhanced the mechanical allodynia of inflamed temporomandibular joint (TMJ) induced by complete Freund's adjuvant. Real-time PCR and immunoblotting demonstrated that TMJ inflammation significantly induced hippocampal TRPV1 expression compared with the control group but failed to induce it in the ovariectomized rats that received no estradiol replacement. In addition, estradiol potentiated TMJ inflammation-induced hippocampal TRPV1 expression in a dose-dependent manner in the ovariectomized rats. In contrast, TRPV1 transcription in amygdala, prefrontal cortex, and thalamus was not affected by TMJ inflammation and estradiol. Immunostaining showed TRPV1 localized in the processes and cytoplasm of pyramidal neurons in CA1-CA3 regions of the hippocampus. Moreover, intrahippocampal injection of TRPV1 antagonists capsazepine and 5Ј-iodoresiniferatoxin into the CA1 region of the hippocampus significantly attenuated allodynia of inflamed TMJ in both nonovariectomized and ovariectomized rats that received estradiol replacement. Our results suggested that hippocampal TRPV1 can modulate central pain processing and estradiol may contribute to the sexual dimorphism of TMD pain sensitivity through upregulation of TRPV1 expression in the hippocampus.

Estrogen-dependent up-regulation of TRPA1 and TRPV1 receptor proteins in the rat endometrium

“…Ovariectomy alleviates suppression of these protein kinases that are known to activate or sensitize TRPV1 (Goswami et al 2011). This was described in neurons where reduced estrogen levels provoke pain/ hyperalgesia (Idris et al 2010, Wu et al 2010, Rossi et al 2014. Ovariectomy also increases non-neuronal TRPV1 and MIF expression (Kastin et al 1992, Oshima et al 2006, Emmerson et al 2009, Idris et al 2010, Wu et al 2010, Kahnamoei 2012, Rossi et al 2014.…”

“…Stimulation of TRPV1 in rat C fibres is dependent on the oestrous cycle favouring oestradiol (Peng et al 2008), and oestradiol may contribute to pain through TRPV1 regulation in the hippocampus (Wu et al 2010). It exerts classical (slow, genomic) effects on Trpv transcription (Hoenderop et al 2005) and can also directly or indirectly stimulate the TRPV1 receptor (Kumar et al 2014).…”

“…Reduced estrogen effects (e.g. after ovariectomy) up-regulate or stimulate TRPV1 and increase pain/hyperalgesia (Idris et al 2010, Wu et al 2010, Rossi et al 2014. According to a well-proven explanation, high estrogen levels determine a female phenotype of signalling pathways downstream of the b 2 adrenergic receptor, such as attenuated protein kinase A and C3 activities (Hucho & Levine 2007).…”

“…Although TRPV1 and TRPA1 have been shown in the human eutopic and ectopic endometrium, their regulation and functional importance are not known (Wu et al 2010, Liu et al 2012, Song et al 2012. Furthermore, there are no data regarding the link between ER activation and the expression of TRP channels and MIF in the normal endometrium related to different hormone levels.…”

Estradiol Promotes M1-like Macrophage Activation through Cadherin-11 To Aggravate Temporomandibular Joint Inflammation in Rats

“…Reverse transcription and realtime PCR were performed as previously described in detail (32). The published sequences of the commercially synthesized primers are as follows: rat b-actin sense/antisense, 59-TGACAGGATGCAGAAGGA-GA-39/59-TAGAGCCACCAATCCACACA-39; rat iNOS sense/antisense, 59-GAGTGAGGAGCAGGTTGAGG-39/59-CCAAGGTGTTGCCCTTT-TT-39; rat IL-1b, sense/antisense 59-CACCTCTCAAGCAGAGCACAG-39/59-GGGTTCCATGGTGAAGTCAAC-39; rat TNF-a sense/antisense, 59-CCAGGTTCTCTTCAAGGGACAA-39/59-CTCCTGGTATGAAATGG-CAAATC-39 (11).…”