Editors' ChoicePain

Why women feel more pain

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Sci. Signal.  04 Aug 2015:
Vol. 8, Issue 388, pp. ec212
DOI: 10.1126/scisignal.aad1342

Signaling from spinal microglia to neurons mediates chronic pain caused by peripheral inflammation or nerve damage. By comparing male and female mice after nerve injury, Sorge et al. identified that chronic pain signaling by microglia is mediated differently between the sexes (see also Brings and Zylka). Although the proliferation of microglia was similar in nerve-injured male and female mice, several chemicals that inhibit microglia activation, including minocycline, reduced mechanical sensitivity (allodynia) only in the male mice. Transiently depleting microglia through intrathecal injection of a conjugated saporin toxin suppressed allodynia in nerve-injured male but not female mice. The expression of the gene encoding the purinergic receptor P2X4R in microglia, previously shown to mediate neuropathic pain in male mice, was increased after nerve injury in male but not female mice. Neither inhibiting P2X4R nor key microglia-to-neuron mediators (the kinase p38 MAPK or the neurotrophin BDNF) reduced allodynia in female mice. In addition to microglia, adaptive T cells are also activated after nerve injury. Minocycline reduced allodynia in nerve-injured female nude or Rag1–/– mice, which lack T and B cells. Adoptive splenocyte transfer prevented minocycline-mediated alleviation of allodynia in female Rag1–/– mice. Together these data suggest that T cells mediate allodynia in female mice, whereas microglia mediate allodynia in male mice, and that females can switch to the microglial pathway in the absence of T cells. Male castration prevented the efficacy of minocycline against allodynia, whereas subcutaneous administration of testosterone reinstated its efficacy in gonadectomized male or enabled minocycline to reduce allodynia in gonadectomized female mice, suggesting that testosterone contributes to the male-specific microglial involvement in allodynia. In T cells, testosterone increases the abundance of the α isoform of the receptor PPAR and decreases the γ isoform. T cells that infiltrate the spine after nerve injury predominantly express PPARγ. An antagonist of PPARγ but not one of PPARα alleviated nerve-injury-induced allodynia in female mice. Thus, gender may dictate distinct therapeutic strategies for patients with chronic neuropathic pain.

R. E. Sorge, J. C. S. Mapplebeck, S. Rosen, S. Beggs, S. Taves, J. K. Alexander, L. J. Martin, J.-S. Austin, S. G. Sotocinal, D. Chen, M. Yang, X. Q. Shi, H. Huang, N. J. Pillon, P. J. Bilan, Y. Tu, A. Klip,R.-R. Ji, J. Zhang, M. W. Salter, J. S. Mogil, Different immune cells mediate mechanical pain hypersensitivity in male and female mice. Nat. Neurosci. 18, 1081–1083 (2015). [PubMed]

V. E. Brings, M. J. Zylka, Sex, drugs, and pain control. Nat. Neurosci. 18, 1059–1060 (2015). [PubMed]