Article Figures & Data
Figures
- Figure 1.
Effect of pregnancy on persistent pain and its sensitivity to reversal by minocycline. A, B, Mechanical allodynia produced by CFA (A) and SNI (B) is reversed by intrathecal minocycline (MCL) in male and early-pregnant mice (14 ± 2 d before parturition; P−14), but not nulliparous or postweaning (7 ± 1 d postweaning and 28 d postparturition; P28) female mice. Late-pregnant mice (2 ± 2 d before parturition; P−2) display no mechanical allodynia. Symbols represent mean ± SEM ipsilateral hindpaw withdrawal threshold (g) prepregnancy (baseline; BL), 3 d after CFA (pregnancy/CFA+3), or 7 d after SNI (pregnancy/SNI+7), and 10–120 min after injection of MCL; n = 7–9 mice/condition. C, CFA produces thermal hyperalgesia in nulliparous female but not late-pregnant (P−2) mice. Symbols represent mean ± SEM ipsilateral hindpaw withdrawal latency (s) prepregnancy (BL) and 3 d after CFA (CFA+3); n = 8–10 mice/condition. D, CFA produces spontaneous pain in nulliparous female but not late-pregnant (P−2) mice. Symbols represent mean ± SEM Mouse Grimace Scale score prepregnancy (BL) and 1 d after CFA (CFA+1); n = 7–8 mice/condition. In all cases, male and nulliparous female mice were tested with delays between baseline and subsequent testing equivalent to late-pregnant mice. E, LPS produces allodynia in male and early-pregnant (P−14) mice, but not nulliparous and late-pregnant (P−2) mice. Symbols represent mean ± SEM bilateral hindpaw withdrawal threshold (g) at baseline (BL) and 1–24 h after injection of LPS; n = 6–8 mice/condition. *p < 0.05, **p < 0.01, ***p < 0.001 compared with CFA+3 (in graph A), SNI+7 (in graph B), or BL (in graphs C–E). ● p < 0.05 compared to all other groups at the same time point. ●●●p < 0.001 compared with all other groups at the same time point.
- Figure 2.
Hormone and opioid dependence of pregnancy analgesia. A, B, Simultaneous adminstration of estradiol and progesterone (HSP) produces abolition of mechanical allodynia from CFA (A) and SNI (B). Symbols represent mean ± SEM ipsilateral hindpaw withdrawal threshold (g) at baseline (BL), after ovariectomy (OVX) and osmotic minipump (Pump) implantation, and 14 d after SNI or 3 d after CFA (+14 in both cases); n = 6 mice/hormone group. C, D, Intrathecal injection of naloxone reveals “hidden” mechanical allodynia after CFA (C) or SNI (D). Symbols represent mean ± SEM ipsilateral hindpaw withdrawal threshold (g) prepregnancy (BL), on day 3 after CFA at P−2 (pregnancy/CFA+3), or day 7 after SNI (SNI+7) and day 25 after SNI at P−2 (pregnancy/SNI+25), and 15–120 min after injection of drug; n = 6–9 mice/drug group. **p < 0.01, ***p < 0.001 compared with +11 (graph A), +OVX (graph B), CFA+3 (graph C), or SNI+25 (graph D). ●● p < 0.01 compared to all other groups at the same time point. ●●●p < 0.001 compared with all other groups at the same time point.
- Figure 3.
T-cell dependence of pregnancy analgesia. A, B, Progressive attenuation of SNI-induced mechanical allodynia during pregnancy, and reinstatement after parturition, in CD-1 (A) but not nude (B) mice. Symbols represent mean ± SEM ipsilateral (Ipsi.) and contralateral (Contra.) hindpaw withdrawal threshold (g) at baseline (BL), at day 7 after SNI or sham surgery (SNI+7), and at various time points before (P−x) and after (P+x) parturition; n = 6–8 mice/genotype/surgery. Purple shading indicates duration of pregnancy. C, Attenuation of SNI-induced mechanical allodynia during pregnancy in C57BL/6 but not Rag1−/− mice. Symbols as in A; n = 6 mice/genotype. D, Late-pregnant nude mice display CFA allodynia, indicating a loss of pregnancy analgesia. Symbols represent mean ± SEM ipsilateral hindpaw withdrawal threshold (g) at prepregnancy (BL) and on day 3 after CFA at P−2 (CFA+3); n = 7–10 mice/genotype/condition. E, Adoptive transfer of splenocytes or isolated CD4+ or CD8+ T cells from pregnant CD-1 mice into late-pregnant nude mice blocks CFA allodynia, indicating a restoration of pregnancy analgesia. Symbols as in D; n = 5–8 mice/condition. *p < 0.05, **p < 0.01, ***p < 0.001 compared with SNI+7 (graphs A–C) or BL (graphs D and E). In graph A, asterisks in conditions other than SNI-Ipsi. are omitted for clarity. ●●●p < 0.001 compared with all other groups at the same time point.
- Figure 4.
δ-Opioid receptor dependence of pregnancy analgesia. A, B, Relative expression of the Oprm1, Oprd1, and Oprk1 genes in the DRG (A) and spinal cord (B) of nulliparous and late pregnant CD-1 and nude mice. Error bars indicate mean ± SEM relative expression normalized to nulliparous CD-1 mice. C, Intrathecal injection of naltrindole, but not β-funaltrexamine (β-FNA) or nor-binaltorphimine (nor-BNI), reinstates “hidden” CFA allodynia in late-pregnant mice. Symbols represent mean ± SEM ipsilateral hindpaw withdrawal threshold (g) prepregnancy (BL), on day 3 after CFA at P−2 (pregnancy/CFA+3), and 15–120 min after injection of drug; n = 6–9 mice/drug. D, Pregnancy analgesia is absent in late-pregnant Oprd1−/− mice. Symbols represent mean ± SEM ipsilateral hindpaw withdrawal threshold (g) prepregnancy (BL), at P−7, and 3 d after CFA (P−4/CFA+3); n = 5–8 mice/genotype/condition. *p < 0.05, **p < 0.01, ***p < 0.001 compared with nulliparous CD-1 (graphs A and B), CFA+3 (graph C), or BL (graph D). ●●p < 0.01 compared with all other groups at the same time point.
