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. Author manuscript; available in PMC: 2022 Apr 1.
Published in final edited form as: Pain. 2021 Apr 1;162(4):1116–1125. doi: 10.1097/j.pain.0000000000002116

Figure 5. Sex difference in LMWH-induced hyperalgesia.

Figure 5.

A. Ovariectomy. Groups of female rats underwent ovariectomy, and one group of rats also received 17β-estradiol replacement, 14 days prior to intrathecal injection of antisense (120 μg/20 μL) or mismatch (120 μg/20 μL) ODN for RHAMM mRNA, once a day for three consecutive days. On the fourth day, after the last intrathecal administration of ODN, LMWH (1 μg/5 μL) was injected intradermally, on the dorsum of the hind paw, and mechanical nociceptive threshold evaluated 5, 10, 15, 20, and 30 min later. The magnitude of the mechanical hyperalgesia in ovariectomized female rats was attenuated in those treated with RHAMM antisense ODN, compared to those treated with its mismatch ODN, while ovariectomized females with 17β-estradiol replacement showed a similar response to the gonad intact female group. (F(3,20)=17.93, *p=0.0182, when the LMWH-induced hyperalgesia is compared between RHAMM antisense ODN- and RHAMM mismatch ODN-, 17β-estradiol plus RHAMM antisense ODN- and 17β-estradiol plus RHAMM mismatch ODN-treated groups 15 min after intradermal LMWH; ***p=0.0008, when the LMWH-induced hyperalgesia is compared between RHAMM antisense ODN- and RHAMM mismatch ODN-, 17β-estradiol plus RHAMM antisense ODN- and 17β-estradiol plus RHAMM mismatch ODN-treated groups 20 min after intradermal LMWH; **p=0.0024, when the LMWH-induced hyperalgesia is compared between RHAMM antisense ODN- and RHAMM mismatch ODN-, 17β-estradiol plus RHAMM antisense ODN- and 17β-estradiol plus RHAMM mismatch ODN-treated groups 30 min after intradermal LMWH; two-way repeated-measures ANOVA followed by Holm-Šídák multiple comparison test). n=6 paws per group.

B. GPR30 ODN-treatment. Female rats were treated daily with spinal intrathecal injections of antisense or mismatch ODN (120 μg/20 μl) to GPR30 and RHAMM mRNA, for 3 consecutive days. On the fourth day, LMWH (1 μg/5 μL) was injected intradermally, on the dorsum of the hind paw, and the magnitude of mechanical nociceptive threshold, evaluated over 30 min. LMWH-induced hyperalgesia was significantly attenuated in rats that received antisense to both GPR30 and to RHAMM mRNA (F(3,20)=6.789, **p=0.0094, when the LMWH-induced hyperalgesia is compared between GPR30 antisense ODN + RHAMM antisense ODN- and others-treated groups 20 and 30 min after intradermal LMWH; two-way repeated-measures ANOVA followed by Holm-Šídák multiple comparison test). Antisense ODN to GPR30 alone did not affect the magnitude of LMWH-induced hyperalgesia (data not shown). n=6 paws per group.