Antihyperalgesic effect of HMWH. A, LMWH (1 μg) was injected intradermally on the dorsum of the hindpaw. Ten minutes later, HMWH (1 μg, black circles) or vehicle (open circles) was injected at the same site and the mechanical nociceptive threshold evaluated over time. Significant reversal of LMWH-induced hyperalgesia was observed in the group treated with HMWH (F(1.16) = 83.33, ****p < 0.0001, when both groups are compared, two-way repeated-measures ANOVA, followed by Bonferroni post hoc test). B, Four pronociceptive mediators, PGE2 (100 ng), epinephrine (epi, 100 ng), TNFα (100 ng), or IL-6 (10 ng), were injected intradermally on the dorsum of the hindpaw. Ten minutes after PGE2 and epinephrine, or 30 min after TNFα and IL-6, HMWH (1 μg, black bars) or vehicle (white bars) was injected at the same site. Measurement of the mechanical nociceptive threshold after an additional 30 min showed a significant attenuation of the hyperalgesia induced by all four pronociceptive mediators, in the groups treated with HMWH (PGE2 groups: t(10) = 5.676, ***p = 0.0001; epi groups: t(10) = 4.150, **p = 0.0010; TNFα groups: t(10) = 6.365, ****p < 0.0001; IL-6 groups: t(10) = 5.461, ***p = 0.0001, when the vehicle and HMWH groups are compared, unpaired Student's t test). C, Rats received four intraperitoneal injections of the neurotoxic chemotherapeutic drug paclitaxel (1 mg/kg), once every other day. Evaluation of mechanical nociceptive threshold 24 h after the last injection of paclitaxel showed robust mechanical hyperalgesia. Then HMWH (1 μg, black bar) or vehicle (white bar) was injected intradermally at the site of nociceptive testing on the dorsum of the hindpaw. Mechanical nociceptive threshold was again evaluated 30 min later. Whereas hyperalgesia was still observed in the vehicle-treated group, in the group that received HMWH, it was markedly attenuated (t(10) = 4.677, ###p = 0.0004, when control and HMWH groups are compared, unpaired Student's t test). A, Control group, n = 12 paws; HMWH group, n = 6. B, C, All groups, n = 6 paws.