Estrogen receptor β activation is antinociceptive in a model of visceral pain in the rat

Abstract

The mechanism underlying estrogen modulation of visceral pain remains unclear. Our previous studies indicate that activation of estrogen receptor α (ERα) enhances visceral pain. The purpose of the present study was to investigate the role of estrogen receptor β (ERβ) activation in spinal processing of visceral stimuli. The effects of selective ERβ agonists on the visceromotor response (VMR) and dorsal horn neuronal responses to colorectal distention (CRD) were tested in ovariectomized and intact female rats. The magnitude of the VMR to CRD was significantly attenuated by ERβ agonists diarylpropionitrile (DPN) and WAY-200070 4 hours after subcutaneous injection. Pretreatment with the estrogen receptor antagonist ICI 182,780 obscured the DPN-evoked attenuation. There was no effect of DPN on the VMR at earlier time points. Subcutaneous and spinal administration of DPN attenuated the response of visceroceptive dorsal horn neurons with a comparable time course. DPN attenuated the VMR in intact rats regardless of estrous cycle stage. The time course of effect of ERβ activation on the visceromotor response and neuronal activity is consistent with transcriptional or translational modulation of neuronal activity.

Perspective: Activation of ERβ is antinociceptive in the colorectal distention model of visceral pain, which may provide a therapeutic target to manage irritable bowel syndrome in the clinic.

Figure 1

The VMR to graded intensities colorectal distention are inhibited by ERβ activation. A-D: The VMR before and after subcutaneous injection of vehicle (A, n = 10) or DPN (B: 1.5 mg/kg, n = 11; C: 3 mg/kg, n = 18; D: 5 mg/kg, n = 12). ** p < 0.01, *** p < 0.001 compared with baseline. ## p < 0.01, ### p < 0.001 compared with baseline for same pressure. E, The percent change from baseline in the area under the curve (AUC) to graded intensities of colorectal distention for different doses of DPN. ^§§ p < 0.01 compared with the vehicle group. F, Original electromyogram recording shows the VMR in a rat was inhibited by 3 mg/kg DPN.

Figure 2

ERβ activation does not inhibit the VMR by membrane-initiated rapid signaling. The magnitude of the VMR remained constant when measured every 30 minutes for 2 h following injection of 3 mg/kg DPN (n=12) or vehicle (n=10).

Figure 3

Confirmation of ERβ inhibition of visceral pain. A: The magnitude of the VMR to graded intensities colorectal distention before and 4 h after s.c. injection of the ERβ agonist WAY200070 (10 mg/kg, n = 12). *** p < 0.001 compared with the baseline. # p < 0.05, ## p < 0.01, ### p < 0.001 compared with baseline for same pressure. B: Fifteen minutes pretreatment with the estrogen receptor antagonist ICI 182,780 (10 nmol) obscured the inhibitory effect of 5 mg/kg DPN (n=11) at 4 h. The inset shows the AUC of four graded intensities distention at baseline and 4 h after 5 mg/kg DPN with or without ICI 182,780. ^§§ p < 0.01 compared with baseline in same group. For clarification, error bars are only shown in one direction in panel B.

Figure 4

Exogenous DPN inhibited the VMR in intact rats. The magnitude of the VMR to graded intensities colorectal distention before and 4 h after s.c. injection of ERβ agonist DPN (5 mg/kg) in non-proestrus rats (A, n = 15) and proestrus (B, n = 5) rats. *** p < 0.001 compared with baseline; # p < 0.05, ## p < 0.01, ### p < 0.001 compared with baseline for same pressure.

Figure 5

The response of dorsal horn neurons to graded intensities of colorectal distention 4-7 h after subcutaneous injection of vehicle (n = 12 for Abrupt and n = 11 for Sustained) or DPN (3 mg/kg, n = 22 for Abrupt and n = 14 for Sustained), and after spinal application of DPN (n = 5 for Abrupt and n = 6 for Sustained). A, Abrupt neurons. B, Sustained neurons. * p < 0.05, *** p < 0.001 compared with the vehicle group. # p < 0.05, ## p < 0.01, ### p < 0.001 compared with the vehicle group for same pressure.

Figure 6

The response of dorsal horn neurons to constant pressure (80 mmHg) colorectal distention over the first 2 h following injection of 3 mg/kg DPN (n = 18 for Abrupt; n = 17 for Sustained) or vehicle (n = 13 for Abrupt; n = 11 for Sustained). A, Abrupt neurons. B, Sustained neurons. ** p < 0.01 compared with baseline.