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. 2015 Aug;18(8):1081-3.
doi: 10.1038/nn.4053. Epub 2015 Jun 29.

Different immune cells mediate mechanical pain hypersensitivity in male and female mice

Robert E Sorge  1 , Josiane C S Mapplebeck  2 , Sarah Rosen  3 , Simon Beggs  4 , Sarah Taves  5 , Jessica K Alexander  4 , Loren J Martin  3 , Jean-Sebastien Austin  3 , Susana G Sotocinal  3 , Di Chen  3 , Mu Yang  6 , Xiang Qun Shi  6 , Hao Huang  6 , Nicolas J Pillon  7 , Philip J Bilan  7 , YuShan Tu  8 , Amira Klip  7 , Ru-Rong Ji  5 , Ji Zhang  9 , Michael W Salter  4 , Jeffrey S Mogil  10
Affiliations

Different immune cells mediate mechanical pain hypersensitivity in male and female mice

Robert E Sorge et al. Nat Neurosci. 2015 Aug.

Abstract

A large and rapidly increasing body of evidence indicates that microglia-to-neuron signaling is essential for chronic pain hypersensitivity. Using multiple approaches, we found that microglia are not required for mechanical pain hypersensitivity in female mice; female mice achieved similar levels of pain hypersensitivity using adaptive immune cells, likely T lymphocytes. This sexual dimorphism suggests that male mice cannot be used as proxies for females in pain research.

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Conflict of interest statement

COMPETING FINANCIAL INTERESTS STATEMENT

The authors have no competing interests as defined by Nature Publishing Group, or other interests that might be perceived to influence the results and/or discussion reported in this article.

Figures

Fig. 1
Fig. 1. Mechanical allodynia after nerve injury is reversed by microglial inhibition in male but not female mice
a) Reversal of established SNI-induced mechanical allodynia by intrathecal minocycline (MCL) in male but not female mice (see also Supplementary Fig. 1a). Symbols represent mean ± SEM 50% withdrawal threshold from von Frey filaments before surgery (BL), 7 days after surgery (pre-injection; D7), and 10–120 min post-injection of minocycline (n=4–5 mice/dose/sex). A different set of mice (n=4 mice/sex) were tested similarly, 28 days post-SNI (D28; right side). b) Male but not female mice treated with Mac-1-SAP display significantly reduced SNI allodynia at 4 h post-treatment. Symbols represent mean ± SEM 50% withdrawal threshold from von Frey filaments before surgery (BL), 7 days after surgery, pre-injection (D7), and 1, 2, 4 and 24 h post-SAP (n=11 mice/sex/condition). c) Intrathecal administration of the P2X inhibitor, TNP-ATP, the p38 MAPK inhibitor, SB203580, the NGF/BDNF inhibitor, Y1036, or the BDNF-sequestering fusion protein, TrkB-Fc, all block SNI-induced allodynia in male but not female mice. The NMDA receptor antagonist, APV, blocks allodynia equally in both sexes. Bars represent mean ± SEM percentage of maximal anti-allodynia (see Methods; n=8 mice/sex/drug). d) Development of SNI-induced mechanical allodynia in male and female mice lacking central nervous system microglial BDNF (i.e., with tamoxifen-induced Cre-loxP-mediated deletion of the Bdnf gene in CX3CR1-positive cells). Mutant (Bdnf−/−) male mice fail to develop full allodynia displayed by female Bdnf−/− and wildtype (Bdnf+/+) mice. Symbols represent mean ± SEM absolute withdrawal threshold from von Frey filaments before and 3, 7, 10 and 14 days post-surgery (n=4–8 mice/sex/genotype). *p<0.05, **p<0.01, ***p<0.001 compared to corresponding female mice by t-test.
Fig. 2
Fig. 2. Mechanical allodynia after nerve injury is mediated by adaptive immune cells in female but not male mice
a) Reversal of mechanical allodynia after SNI by intrathecally administered glial inhibitors minocycline (MCL), fluorocitrate (FC) and propentofylline (PPF) in male but not female CD-1 mice, but in immunocompromised nude mice of both sexes. Bars represent mean ± SEM percentage of maximal anti-allodynia (n=4–7 mice/sex/drug/genotype). b) Male-specific reversal of allodynia from the PPARα ligand, fenofibrate (FFB) is blocked by the PPARα antagonist, GW6471, and by castration (TX). Bars as in graph a (n=4–6 mice/sex/condition). c) Female-specific reversal of allodynia from the PPARγ ligand, pioglitazone (PIO) is reversed by the PPARγ antagonist, GW9662, and by testosterone proprionate (TP). Bars as in graph a (n=7–10 mice/sex/condition). *p<0.05, **p<0.01 compared to corresponding female mice by t-test. •p<0.05, ••p<0.01, •••p<0.001 compared to same-sex wildtype (CD-1) or vehicle group by t-test. n.t. = not tested.
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References

    1. Grace PM, Hutchinson MR, Maier SF, Watkins LR. Pathological pain and the neuroimmune interface. Nat Rev Immunol. 2014;14:217–231. - PMC - PubMed
    1. Watkins LR, Maier SF. Glia: a novel drug discovery _target for clinical pain. Nat Rev Drug Discov. 2003;2:973–985. - PubMed
    1. Mogil JS, Chanda ML. The case for the inclusion of female subjects in basic science studies of pain. Pain. 2005;117:1–5. - PubMed
    1. Sorge RE, et al. Spinal cord Toll-like receptor 4 mediates inflammatory and neuropathic hypersensitivity in male but not female mice. J Neurosci. 2011;31:15450–15454. - PMC - PubMed
    1. Tsuda M, et al. P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury. Nature. 2003;424:778–783. - PubMed

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