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. Author manuscript; available in PMC: 2023 Sep 1.
Published in final edited form as: Pain. 2021 Dec 6;163(9):1728–1739. doi: 10.1097/j.pain.0000000000002558

Figure 2. HMWH-induced anti-hyperalgesia in females is sex hormone dependent.

Figure 2.

A. Female rats underwent ovariectomy 14 days prior to receiving oxaliplatin (2 mg/kg, i.v.), on day 0. On day 7, HMWH (1 μg/ 5 μL, i.d.) was injected on the dorsum of the hind paw. Mechanical nociceptive threshold was evaluated before oxaliplatin and 30 min, and 7 days after, and again 30 min after HMWH. Intradermal administration of HMWH attenuates the hyperalgesia induced by oxaliplatin in ovariectomized female rats (F(3,30)= 17.04, ****p<0.0001, when CIPN treated with HMWH was compared to the CIPN vehicle-treated group; two-way ANOVA followed by Bonferroni’s post hoc comparisons test). n= 6 per group.

B. Another group of female rats underwent ovariectomy 14 days prior to receiving paclitaxel (1 mg/kg, i.p.), every other day for a total of 4 doses (days 0, 2, 4 and 6). Seven days later, rats were treated with HMWH (1 μg/ 5 μL, i.d.) on the dorsum of the hind paw. Mechanical nociceptive threshold was evaluated before paclitaxel, and on days 1, 3, 5 and 7 after, and then 30 min after HMWH. Intradermal administration of HMWH attenuates the hyperalgesia induced by paclitaxel in ovariectomized rats (F(5,50)= 9.61, ****p<0.0001, when CIPN treated with HMWH was compared to the CIPN vehicle-treated group; two-way ANOVA followed by Bonferroni’s post hoc comparisons test). n= 6 per group.

C. Female rats received oxaliplatin (2 mg/kg, i.v.) on day 0. Four days later, they were treated with an oligodeoxynucleotide (ODN) antisense or mismatch (120 μg/ 20 μL, i.t.) for GPR30 mRNA, daily for 3 consecutive days. On day 7, approximately 24 h after the last dose of ODN, HMWH (1 μg/ 5 μL, i.d.) was injected on the dorsum of the hind paw. Mechanical nociceptive threshold was evaluated before oxaliplatin and 30 min, 4 and 7 days after its administration, and then 30 min after HMWH. Oxaliplatin similarly decreases mechanical nociceptive threshold in both GPR30 antisense- and mismatch-treated rats. Intradermal administration of HMWH attenuates the hyperalgesia induced by oxaliplatin in the GPR30 antisense-treated group (F(4,40)= 15.99, ****p<0.0001, when CIPN treated with HMWH was compared to the CIPN vehicle-treated group; two-way ANOVA followed by Bonferroni’s post hoc comparisons test). n= 6 per group.

D. Female rats received paclitaxel, administered intraperitoneally (1 mg/kg, i.p.) every other day for a total of 4 doses (days 0, 2, 4 and 6). Four days after the 1st paclitaxel injection, rats were treated with antisense or mismatch ODN antisense for GPR30 mRNA (120 μg/ 20 μL, i.t.), daily for 3 consecutive days. On day 7, approximately 24 h after the last ODN dose and the last dose of paclitaxel, HMWH (1 μg/ 5 μL, i.d.) was injected on the dorsum of the hind paw. Mechanical nociceptive threshold was evaluated before paclitaxel, and on day 1, 3, 5 and 7 after its administration, and then 30 min after HMWH. In both GPR30 antisense- and mismatch-treated groups, paclitaxel decreases mechanical nociceptive threshold. In the group treated with ODN antisense to GPR30 mRNA, intradermal administration of HMWH attenuates the hyperalgesia induced by paclitaxel (F(5,50)= 8.75, ****p<0.0001, when CIPN treated with HMWH was compared to the CIPN vehicle-treated group; two-way ANOVA followed by Bonferroni’s post hoc comparisons test). n= 6 per group.