Figure 6.
PEA administration ameliorates acute hyperalgesia in HbSS mice. (A) Pretreatment schema: mice are treated with PEA (IP, 20 mg/kg per day) for 14 days; H/R, hypoxia (3 hours at 8% O2) followed by reoxygenation (1 hour at ∼21% O2, normoxia), is incited on days 5 and 7; and hyperalgesia testing is performed at BL, 1 hour and 72 hours after start of daily treatment, 1 hour and 24 hours after first and second incitement of H/R, and finally on day 14 after start of treatment. (B-C) PEA treatment significantly reduces mechanical and cold hyperalgesia and prevents H/R-induced acute hyperalgesia, which is significantly increased in Veh-treated HbSS mice compared with BL. (D) PEA-treated HbSS mice also show increased grip force suggestive of less musculoskeletal hyperalgesia after second incitement of H/R compared with Veh treatment. (E) H/R-responsive treatment schema: mice are treated with a single dose of PEA (IP, 20 mg/kg) immediately after first incitement of H/R; H/R is incited on days 0 and 2; and hyperalgesia testing is performed at BL, 1 hour and 24 hours after first and second incitement of H/R, and finally on day 9 after start of experiment. (F-G) PEA treatment significantly reduces H/R-evoked mechanical and cold hyperalgesia 1 hour and 24 hours after incitement compared with Veh treatment and BL, however the second incitement of H/R significantly increases mechanical and cold hyperalgesia compared with BL regardless of treatment. (H) PEA treatment also shows increased grip force suggestive of less musculoskeletal hyperalgesia after second incitement of H/R in sickle cell mice compared with Veh treatment. Mean ± SD. In panels B-D,F-H, data were analyzed using repeated measures 2-way ANOVA and the Tukey post hoc multiple comparisons test. ∗Indicates difference compared with time-matched Veh; †indicates difference compared with SS-PEA BL; ‡indicates difference compared with SS-Veh BL. ∗,†,‡P < .05; ∗∗,††,‡‡P < .01; ∗∗∗,†††P < .001. Age: 3.5 to 5.0 months. For panels B-D: PEA female, HbAA Veh, n = 9; HbAA 20 mg/kg, n = 6; HbSS Veh, n = 10; HbSS 20 mg/kg, n = 10; panels F-H: HbSS Veh, n = 5; HbSS 20 mg/kg, n = 6. BW, body weight; HR, hypoxia/reoxygenation; PWF, paw withdrawal frequency; VF, von Frey.

PEA administration ameliorates acute hyperalgesia in HbSS mice. (A) Pretreatment schema: mice are treated with PEA (IP, 20 mg/kg per day) for 14 days; H/R, hypoxia (3 hours at 8% O2) followed by reoxygenation (1 hour at ∼21% O2, normoxia), is incited on days 5 and 7; and hyperalgesia testing is performed at BL, 1 hour and 72 hours after start of daily treatment, 1 hour and 24 hours after first and second incitement of H/R, and finally on day 14 after start of treatment. (B-C) PEA treatment significantly reduces mechanical and cold hyperalgesia and prevents H/R-induced acute hyperalgesia, which is significantly increased in Veh-treated HbSS mice compared with BL. (D) PEA-treated HbSS mice also show increased grip force suggestive of less musculoskeletal hyperalgesia after second incitement of H/R compared with Veh treatment. (E) H/R-responsive treatment schema: mice are treated with a single dose of PEA (IP, 20 mg/kg) immediately after first incitement of H/R; H/R is incited on days 0 and 2; and hyperalgesia testing is performed at BL, 1 hour and 24 hours after first and second incitement of H/R, and finally on day 9 after start of experiment. (F-G) PEA treatment significantly reduces H/R-evoked mechanical and cold hyperalgesia 1 hour and 24 hours after incitement compared with Veh treatment and BL, however the second incitement of H/R significantly increases mechanical and cold hyperalgesia compared with BL regardless of treatment. (H) PEA treatment also shows increased grip force suggestive of less musculoskeletal hyperalgesia after second incitement of H/R in sickle cell mice compared with Veh treatment. Mean ± SD. In panels B-D,F-H, data were analyzed using repeated measures 2-way ANOVA and the Tukey post hoc multiple comparisons test. ∗Indicates difference compared with time-matched Veh; †indicates difference compared with SS-PEA BL; ‡indicates difference compared with SS-Veh BL. ∗,†,‡P < .05; ∗∗,††,‡‡P < .01; ∗∗∗,†††P < .001. Age: 3.5 to 5.0 months. For panels B-D: PEA female, HbAA Veh, n = 9; HbAA 20 mg/kg, n = 6; HbSS Veh, n = 10; HbSS 20 mg/kg, n = 10; panels F-H: HbSS Veh, n = 5; HbSS 20 mg/kg, n = 6. BW, body weight; HR, hypoxia/reoxygenation; PWF, paw withdrawal frequency; VF, von Frey.

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