Sex-related differences in NMDA-evoked rat masseter muscle afferent discharge result from estrogen-mediated modulation of peripheral NMDA receptor activity

Abstract

In the present study, the hypothesis that sex-related differences in glutamate-evoked rat masseter muscle afferent discharge may result from estrogen-related modulation of peripheral N-methyl-d-aspartate (NMDA) receptor activity and/or expression was tested by examining afferent fiber discharge in response to masseter injection of NMDA and the expression of NR2A/B subunits by masseter ganglion neurons in male and female rats. The results showed that injection of NMDA into the masseter muscle evoked discharges in putative mechanonociceptive afferent fibers and increased blood pressure that was concentration-dependent, however, a systemic action of NMDA appeared responsible for increased blood pressure. NMDA-evoked afferent discharge was significantly greater in female than in male rats, was positively correlated with plasma estrogen levels in females and was significantly greater in ovariectomized female rats treated with a high dose (5 mug/day) compared with a low dose (0.5 mug/day) of estrogen. Pre-treatment of high dose estrogen-treated-ovariectomized female rats with the Src tyrosine kinase inhibitor PP2 did not affect NMDA-evoked afferent discharge. NMDA-evoked afferent discharge was attenuated by the antagonists ketamine and ifenprodil, which is selective for NR2B containing NMDA receptors. Fewer masseter ganglion neurons expressed the NR2A (16%) subunit as compared with the NR2B subunit (38%), which was expressed at higher frequencies in intact female (46%) and high dose estrogen-treated ovariectomized female (60%) rats than in male (31%) rats. Taken together, these results suggest that sex-related differences in NMDA-evoked masseter afferent discharge are due, at least in part, to an estrogen-mediated increase in expression of peripheral NMDA receptors by masseter ganglion neurons in female rats.

Differential Effects of Estradiol on Encoding Properties of TMJ Units in Laminae I and V at the Spinomedullary Junction in Female Rats

“…For example, when tested directly, glutamate-evoked TMJ (Cairns et al 2001b) or masseter muscle (Cairns et al 2001a) afferent nerve activity did not vary over the estrous cycle, although responses in females were greater than those in males. Only after longterm exposure to high circulating levels of E2 (Ͼ60 pg/ml) were the responses to NMDA injections by masseter muscle nerve afferents increased (Dong et al 2007).…”

A new hypothesis of sex-differences in temporomandibular disorders: Estrogen enhances hyperalgesia of inflamed TMJ through modulating voltage-gated sodium channel 1.7 in trigeminal ganglion?

“…Acute TMJ inflammation induced by mustard oil injection produced greater fos-like immunoreactivity in proestrous compared to diestrous female rats at the major terminal zone for sensory afferents innervating the TMJ, indicating that TMJ inflammation produces greater neural activation when ovarian hormones are higher [26]. Estradiol also dose-dependently increased trigeminal afferent discharge induced by NMDA injection into the masseter muscle in ovariectomized rats [27]. Moreover, estrogen increases the excitability of rat TMJ afferents and exacerbates the inflammation-induced sensitization of these sensory neurons [9].…”

Influence of pro-algesic foods on chronic pain conditions

“…Intramuscular injection of glutamate into the masseter muscle has also been shown to evoke brief (< 10 min) nociceptor discharges as well as induce a prolonged period (> 3 hours) of mechanical sensitization in cranial muscle nociceptors that are also mediated through activation of peripheral NMDA receptors [21][22][23]. Thus, the pain sensitizing effects of MSG appear to be mediated, in part, through activation of peripheral NMDA receptors expressed by a subgroup of masticatory muscle nociceptors [24][25][26].…”