Telemetric assessment of referred vaginal hyperalgesia and the effect of indomethacin in a rat model of endometriosis

Abstract

Symptoms of endometriosis (ENDO), among others, include pelvic/abdominal and muscle pain. Non-steroidal anti-inflammatory agents are first-line treatment for this pain. Similar to women, rats with surgically induced ENDO, but not its surgical control, exhibit vaginal hyperalgesia, which in rats is evidenced by a decreased threshold for the visceromotor response (VMR) induced by vaginal distention. Here we assess the VMR in rats with implanted probes that telemetrically transmit EMG activity from the abdominal muscle. The feasibility and sensitivity of this technique for monitoring the VMR threshold across the estrous cycle and the influence of Indomethacin on ENDO-induced vaginal hyperalgesia were evaluated. VMR thresholds in response to vaginal distention with an infusion pump were measured in different estrous stages. Indomethacin (5 or 10 mg/kg i.p. or s.c.) was injected in proestrus rats and 40-60 min later the VMR threshold was measured. The VMR threshold varied across the estrous cycle only in ENDO rats, being lowest in proestrus. Indomethacin increased this threshold in proestrus ENDO rats. These results show that telemetric assessment of the VMR is a sensitive tool, suitable for long-term studies in conscious rats. The results with this technique also suggest that ENDO-associated vaginal hyperalgesia involves COX activity, the feature that also underlies inflammatory pains.

Keywords: PGE2; analgesia; prostaglandins; uterus.

Figure 1

(A) Experimental setting for recording of the visceromotor response (VMR) to vaginal stimulation with the Ponemah Telemetric System (DSI, St. Paul, MN, USA). Pressure in the vaginal balloon was generated by an infusion pump. The EMG signal from the electrode implanted in the abdominal muscle was converted into radio signals by the telemetric probe and transmitted to a receiver connected to the acquisition module of the Ponemah System and synchronized with the incoming signal from the pressure transducer. (B) A recording of EMG activity during vaginal distension before and after 10 mg/kg Indomethacin (i.p.) injection in the same rat. The first arrow shows the beginning of vaginal distention, and the second arrow shows the VMR threshold. The VMR threshold increased after Indomethacin.

Figure 2

Estrous variations in VMR to vaginal distention (Volume threshold) in rats >8 weeks after ENDO or shamENDO surgery. Baseline thresholds were measured across the estrous cycle over 3–5 weeks and then averaged for each estrous stage (i.e., in metestrus DI, diestrus DII, proestrus P, and estrus E). ANOVA showed that thresholds in ENDO rats were significantly different than thresholds in shamENDO rats (p < 0.001). *p < 0.005; **p < 0.001, compared to P.

Figure 3

Effects of i.p. injection of two doses of Indomethacin and vehicle on the VMR threshold in rats after ENDO or Sham ENDO surgery. Although vehicle produced a small increase in the VMR threshold, this increase was not significantly different from baseline. The increase produced by 10 mg/kg of Indomethacin was significantly higher than the increase produced by vehicle. *p < 0.05 compared to vehicle.

Figure 4

Effect of 10 mg/kg of Indomethacin injected s.c. in the neck on the VMR threshold. *p < 0.05 compared to vehicle.