Estrogen alters spinal NMDA receptor activity via a PKA signaling pathway in a visceral pain model in the rat

Abstract

Pain symptoms in several chronic pain disorders in women, including irritable bowel syndrome, fluctuate with the menstrual cycle suggesting a gonadal hormone component. In female rats, estrogens modulate visceral sensitivity although the underlying mechanism(s) are unknown. In the present study the effects of 17-β estradiol on N-methyl-D-aspartate (NMDA) receptor signaling of colorectal nociceptive processing in the spinal cord were examined. Estrogen receptor alpha and the NR1 subunit of the NMDA receptor are co-expressed in dorsal horn neurons, supporting a direct action of estradiol on NMDA receptors. Intrathecal administration of the NMDA receptor antagonist D(−)-2-amino-5-phosphonopetanoic acid (APV) dose-dependently attenuated the visceromotor response with greater potency in ovariectomized (OVx) rats compared to OVx with estradiol replacement (E2) rats. Estradiol significantly increased protein expression of NR1 in the lumbosacral spinal cord compared to OVx rats. Colorectal distention significantly increased phosphorylation of NR1ser-897, a PKA phosphorylation site on the NR1 subunit in E2, but not OVx rats. Intrathecal administration of a PKA inhibitor significantly attenuated the visceromotor response, decreased NR1 phosphorylation and increased the potency of APV to attenuate the visceromotor response compared to vehicle-treated E2 rats. These data suggest that estradiol increases spinal processing of visceral nociception by increasing NMDA receptor NR1 subunit expression and increasing site specific receptor phosphorylation on the NR1 subunit contributing to an increase in NMDA receptor activity.

Estrogenic influences in pain processing

“…the response to a noxious stimulus applied to the rodent's tail, which is considered to be a spinal reflex (Irwin et al, 1951), is influenced by estrogens (Frye et al, 1992;Gordon and Soliman, 1996). Albeit this effect could be due to a facilitating effect at the supraspinal level, in vivo electrophysiological experiments demonstrate that the modulation of the response takes place in the spinal cord, something that also has been shown for the estrogenic regulation of visceral sensitivity (Ji et al, 2003;Ji et al, 2011;Tang et al, 2008). Pregnancy-induced analgesia in the rat also has an unambiguous spinal component since intrathecal but not intracerebroventricular administration of naloxone (Sander et al, 1989) attenuates it.…”

“…Their results suggest that endogenous estrogen may reduce glutamatergic transmission by activating ER in the spinal dorsal horn, thereby inhibiting pain responses. On the other hand, a single subcutaneous injection of estradiol has also been shown to increase spinal NMDA-receptor activity and the expression of spinal NMDA-receptors in response to visceral pain in ovariectomized rats (Tang et al, 2008). A direct pain-modulating action of estrogens at the spinal level is further supported by many behavioral studies.…”

“…In the hot plate test, estradiol significantly increases pain sensitivity in ovariectomized rats in some experiments (Gordon and Soliman, 1996;Ratka and Simpkins, 1991) and a reduction in tail-flick latencies after estradiol treatment has also been reported (Frye et al, 1992). Vocalization thresholds to noxious pressure stimuli increase during periods of low estrogen in the normally cycling rat (Kayser et al, 1996) and estradiol has also been shown to increase visceral nociception in response to colorectal distention in rats (Ji et al, 2005;Tang et al, 2008).…”

Mechanisms of Stress-induced Visceral Pain

“…104 Another estrogenmediated mechanism that could drive visceral hypersensitivity is via the induction of µ-opioid receptor internalization within the medial preoptic nucleus and the posterodorsal medial amygdala. 105 At the level of the spinal cord, multiple studies have characterized estrogen as an important modulator of visceral nociceptive signaling, specifically through an effect on the N-methyl-D-aspartate receptor, 106 metabotropic glutamate receptor 2 (mGluR2), 107 and ionotropic glutamate receptor subunit 2B activity 108 within the spinal cord.…”

Is There a Role for Acupuncture in Endometriosis Pain, Or ‘endometrialgia’?

“…55;56 ( Fig 3a) These receptors are coupled to intracellular kinases, protein kinase A(PKA), protein kinase C (PKC), the mitogen activated protein kinases (MAPKs) extracellular signal regulated kinase (ERK) and p38 as well as the c-Jun amino-terminal kinase 1 (JNK), in the cytoplasm of the terminal. 57 The kinases phosphorylate amino acids, for example serine and threonine, which result in a change in the proteins ACUPUNCTURE IN MEDICINE 2008;26(2):94-110.…”