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.

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The existence of a sex difference in several chronic pain syndromes and the fluctuation of symptoms during the menstrual cycle strongly suggest sex hormones are involved in pain processing. The mechanisms underlying these changes are not well understood. Using the colorectal distention model in the rat, we previously reported a sex difference in the response to distention [Ji Y, Murphy AZ, Traub RJ (2006) Sex differences in morphine induced analgesia of visceral pain are supraspinally and peripherally mediated. Am J Physiol Regul Integr Comp Physiol 291:R307-R314] and that ovariectomy decreased the responses to distention while estrogen replacement reversed the decrease [Ji Y, Murphy AZ, Traub RJ (2003) Estrogen modulates the visceromotor reflex and responses of spinal dorsal horn neurons to colorectal stimulation in the rat. J Neurosci 23:3908-3915], suggesting estrogen increases visceral nociception. In the present study we tested the hypothesis that the visceromotor response to colorectal distention fluctuates with the estrous cycle. Three measurements (vaginal smears, uterine tube weight and plasma estrogen concentration) were used to determine the estrous phase. Comparison of the visceromotor response threshold and magnitude was made between proestrus and metestrus/diestrus. Our experiment demonstrated that the distention threshold was significantly lower in proestrus (median: 15 mm Hg) as compared with metestrus/diestrus (median: 25 mm Hg); and the magnitude of the visceromotor response to graded intensities of colorectal distentions (20, 40, 60, 80 mm Hg) was significantly higher in proestrus. The results indicate that the visceromotor response fluctuates with estrous phase, providing evidence for endogenous estrogen modulation of visceral nociceptive processing that could contribute to sex differences.

Background & Aims-Chronic visceral hyperalgesia is considered an important pathophysiological symptom in irritable bowel syndrome (IBS); previous gastrointestinal inflammation is a potent etiological factor for developing IBS. Although there are several animal models of adult visceral hypersensitivity following neonatal perturbation or acute colonic inflammation, there is no suitable model of post-inflammatory chronic visceral hyperalgesia. The aim of this study was to establish a model of chronic visceral hyperalgesia following colonic inflammation in the rat.

We previously reported that 17β -estradiol (E2) is pronociceptive in a visceral pain model in the rat. Subcutaneously (s.c.) administered E2 reversed the decrease in the colorectal distention (CRD)-evoked visceromotor response produced by ovariectomy (OVx) and CRD-induced nociceptive responses were greater in proestrous rats compared to met/diestrous rats. The site of action, the type of estrogen receptors activated and the possible intracellular signaling pathway involved are yet to be established. In the present study, intrathecal (i.t.) E2 administered to OVx rats mimicked the effects of s.c. E2, suggesting spinal E2 receptors are involved. This is further supported by the observations that the anti-estrogen ICI 182,780 injected i.t. in intact female rats significantly decreased the visceromotor response to CRD, the response of colonic afferents was not affected by OVx and colonic afferents did not label for estrogen receptor α (ERα). The ERα selective agonist, 4,4',4"-[4-propyl-(1H)-pyrazole-1,3,5-triyl]tris-phenol (PPT; s.c. or i.t.) facilitated the visceromotor response similar to E2, suggesting ERα activation is involved in mediating the pronociceptive effect of E2. PPT (s.c. or i.t.) increased the response of spinal dorsal horn neurons to CRD, indicating a spinal site of action. In addition, s.c. E2 or PPT increased CRD-induced spinal extracellular-signal-regulated kinase (ERK) phosphorylation that was not observed in OVx rats and a mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitor blocked facilitation of the visceromotor response by PPT. Taken together, the present study demonstrates that spinal ERα mediates the pronociceptive effect of E2 on visceral signal processing through activation of the MAPK pathway.

Wang, Gexin, Bin Tang, and Richard J. Traub. Differential processing of noxious colonic input by thoracolumbar and lumbosacral dorsal horn neurons in the rat. J Neurophysiol 94: 3788 -3794, 2005. First published August 10, 2005; doi:10.1152/jn.00230.2005. Previous studies suggest the lumbosacral (LS) spinal cord processes acute colorectal stimuli whereas the thoracolumbar (TL) and LS spinal segments process inflammatory stimuli. In this study, the effects of colorectal distention (CRD) on TL and LS dorsal horn neuronal activity were recorded in Nembutal-anesthetized male rats both with and without colonic inflammation. Both single cells (before and after inflammation) and populations (multiple cells from noninflamed or inflamed rats) were studied. CRD-responsive neurons had excitatory Abrupt (ON-OFF with stimulus) or Sustained (prolonged after discharge) responses or were Inhibited by CRD. In noninflamed rats, a significantly greater percentage of LS neurons (63% Abrupt, 27% Sustained) were excited by CRD than TL neurons (61% Abrupt, 3% Sustained). The remaining cells were Inhibited (10% LS, 36% TL). LS Abrupt neurons had lower thresholds and greater response magnitudes to CRD compared with TL Abrupt neurons. After colonic inflammation, TL neurons became more excitable: the percentage of Inhibited neurons decreased, the response magnitude of Abrupt neurons increased, and the threshold decreased. In contrast, in single-cell recordings, the response of LS Sustained neurons increased, whereas LS Abrupt neurons decreased. These data suggest that in noninflamed rats, the net response to CRD of TL visceroceptive spinal sensory neurons is less than that of LS neurons. Colonic inflammation increases the net response of TL neurons and differentially modulates the response of LS neurons. These differences may contribute to the functional dichotomy between the TL and LS spinal segments in processing acute and inflammatory colorectal pain. I N T R O D U C T I O NA unique feature of the viscera is dual innervation by sensory afferent fibers projecting in the same nerves as sympathetic (splanchnic, hypogastric) and parasympathetic (vagal, pelvic) efferents. In the rat, the descending colon and rectum are innervated by primary afferent fibers projecting in the pelvic nerve to the L6 -S2 spinal cord segments and hypogastric/lumbar colonic nerves projecting to the T13-L2 spinal cord (Mayer and Gebhart 1994; Mayer and Raybould 1990; Nadelhaft and Booth 1984; Ness and Gebhart 1988; Traub et al. 1999). However, the physiological role of this dual innervation in visceral nociceptive processing is unclear. Previous studies suggest that the lumbosacral (LS) and thoracolumbar (TL) spinal cord segments process acute and inflammatory pain from the colon and rectum differently. In humans, referred pain evoked by colorectal distention (CRD) in normal volunteers is perceived in the sacral dermatomes, whereas patients with irritable bowel syndrome or Crohn's disease report referred pain expanding into the TL dermatomes (Bernstein et al. 199...

The contribution of estrogen and progesterone to colorectal hyperalgesia was examined in female rats. The electromyogram recorded from the abdominal wall (visceromotor response, vmr) and the discharge of lumbosacral dorsal horn neurons to colorectal distention (CRD) were measured in intact female, ovariectomized (OVx) and estradiol replaced OVx (E2; 50mug, 48h) rats with and without colonic inflammation. Colorectal hyperalgesia was transient in intact rats, but persisted at least 4h in E2 and OVx rats. The magnitude of hyperalgesia in E2 rats was greater than OVx which was greater than intact rats. Dorsal horn neurons that responded to CRD with an Abrupt (on and off with stimulus) excitatory discharge showed similar sensitivity to estradiol as the vmr following colonic inflammation. In contrast, inflammation did not increase the magnitude of response of excitatory neurons with sustained afterdischarges in any of the treatment groups. Intact female rats have a comparable plasma estrogen concentration to E2 rats, suggesting the difference in responses may have been due to antinociceptive effects of progesterone. This was tested by administering E2+/- progesterone (1mg) and measuring the vmr. Progesterone reduced the facilitation of the vmr produced by E2 before and following colonic inflammation. The present study suggests that estrogen replacement enhances visceral signal processing following colonic inflammation. Furthermore, progesterone may counteract the effects of estrogen on colorectal sensitivity.

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