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While the onset of mechanical hyperalgesia induced by endothelin-1 was delayed in female rats, compared to males, the duration was much longer. Given that the repeated test stimulus used to assess nociceptive threshold enhances hyperalgesia, a phenomenon we have referred to as stimulus-induced enhancement of hyperalgesia, we also evaluated for sexual dimorphism in the impact of repeated application of the mechanical test stimulus on endothelin-1 hyperalgesia. In male and female rats, endothelin-1 induced hyperalgesia is already maximal at 30 min. At this time stimulus-induced enhancement of hyperalgesia, which is observed only in male rats, persisted for 3-4h. In contrast, in females, it develops only after a very long (15 day) delay, and is still present, without attenuation, at 45 days. Ovariectomy eliminated these differences between male and female rats. These findings suggest marked, ovarian-dependent sexual dimorphism in endothelin-1 induced mechanical hyperalgesia and its enhancement by repeated mechanical stimulation.
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Figures
Figure 1. Latency to onset of endothelin-induced…
Figure 1. Latency to onset of endothelin-induced mechanical hyperalgesia
Paw withdrawal thresholds are measured at…
Figure 1. Latency to onset of endothelin-induced mechanical hyperalgesia
Paw withdrawal thresholds are measured at one-minute inter-trial intervals after the intradermal (i.d.) administration of endothelin-1 (100 ng) or saline, to determine latency to onset of hyperalgesia. Each point represents the average reduction in paw withdrawal threshold in % (A) or in grams (B). Endothelin produced significant hyperalgesia in male, female and OVX females, (all p<0.0001, n = 6/group). In intact females, the onset of hyperalgesia was delayed, a significant reduction first occurred at four minutes. Saline treatment showed no significant change in the paw withdrawal threshold (p > 0.05).
Figure 2. Time course of endothelin-induced mechanical…
Figure 2. Time course of endothelin-induced mechanical hyperalgesia
A & B . Each point represents…
Figure 2. Time course of endothelin-induced mechanical hyperalgesia
A & B. Each point represents the average of 4 separate measurements from each paw (n = 6/group), with a 5 minute inter-stimulus interval, measured at different time points (1–45 days); the last reading corresponds to the time point indicated. On days 5 and 10, when all four readings are averaged there is a time dependent hyperalgesia (p<0.001) but no sex dependent difference (p > 0.05). However, from day 15 to 45 there was a significant effect of time and sex (A (%) and B (g), for both p < 0.001). C & D. Each point represents the average of the first of the four readings following administration of endothelin (100 ng, i.d., n = 6/group), at the different time points (1–45 days). In all three groups (male, female and OVX female rats), endothelin (100 ng, i.d.) induced mechanical hyperalgesia, significant for 10 days (all p < 0.0001, C (%) and D (g)) and returned to baseline by day 25. There was no sex dependent difference when first readings were compared (p > 0.05). In saline treated male and female rats, from day 1–45, no significant change in paw withdrawal threshold was observed (p > 0.05).
Figure 3. Effect of repeated mechanical stimulation…
Figure 3. Effect of repeated mechanical stimulation on endothelin-induced hyperalgesia, (0.5–3 hour - expanded results)
Figure 3. Effect of repeated mechanical stimulation on endothelin-induced hyperalgesia, (0.5–3 hour - expanded results)
Four paw withdrawal thresholds were measured with an inter-stimulus interval of 5 min, at different time points (0.5–3 hr.), in male, female and OVX female rats, the last reading corresponding to the time point indicated on the graph. Paw withdrawal threshold (average of 4 readings) at each point is plotted separately to depict the effect of a repeated stimulus. Repeated stimulation progressively increased the hyperalgesia at 0.5 hr. (A (%), B (g), (p
Figure 4. Effect of repeated mechanical stimulation…
Figure 4. Effect of repeated mechanical stimulation on endothelin-induced hyperalgesia, (Day 5–15 - expanded results)
Figure 4. Effect of repeated mechanical stimulation on endothelin-induced hyperalgesia, (Day 5–15 - expanded results)
Four paw withdrawal thresholds were measured with an inter-stimulus interval of 5 min, on day 5, 10 and 15, in male, female and OVX female rats. Each stimulus effect is separately plotted to depict the repeated stimulus effect. There was no repeated stimulus induced or sex dependent (p > 0.05) difference in hyperalgesia on day 5 (A (%), B (g)) in all three groups (male, female and OVX female)) of rats. On day 10 (C (%), D (g)), there was a significant effect of repeated stimulus (p
Figure 5. Effect of repeated mechanical stimulation…
Figure 5. Effect of repeated mechanical stimulation on endothelin-induced hyperalgesia, (Day 20–45 - expanded results)
Figure 5. Effect of repeated mechanical stimulation on endothelin-induced hyperalgesia, (Day 20–45 - expanded results)
Four paw withdrawal thresholds were measured with an inter-stimulus interval of 5 min, on day 20, 25, 30 and 45, in male, female and OVX female rats. Each stimulus effect is separately plotted to depict the repeated stimulus effect as well as to compare the effect in different groups. From day 20–45 there was both stimulus induced (day 20 A (%), B (g), p
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