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Estrogen modulation of peripheral pain signal transduction: involvement of P2X3 receptors

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Abstract

There is evidence that gonadal hormones may affect the perception of painful stimulation, although the underlying mechanisms remain unclear. This investigation was undertaken to determine whether the adenosine 5′-triphosphate (ATP) receptor subunit, P2X3, is involved in the modulatory action of estrogen in peripheral pain signal transduction in dorsal root ganglion (DRG). The mechanical pain behavior test, real-time quantitative reverse transcription–polymerase chain reaction analysis, and Western blot methods were used to determine the mean relative concentrations and functions of P2X3 receptors in DRG in sham, ovariectomized (OVX), and estradiol replacement (OVX+E2) female rats and in sham and orchiectomized male rats. The mechanical hyperalgesia appeared after ovariectomy, which was subsequently reversed after estradiol replacement, whereas it was not observed after orchiectomy in male rats. Plantar injection of 2′(3′)-O-(2,4,6-trinitrophenyl) ATP (TNP-ATP), a P2X3 and P2X2/3 receptor antagonist, resulted in an increase of the pain threshold force in OVX rats while had no effect on sham rats. Furthermore, A-317491, a selective P2X3/P2X2/3 receptor antagonist, significantly reversed the hyperalgesia of OVX rats. Injection of ATP into the plantars also caused a significant increase of the paw withdrawal duration in OVX rats compared with that seen in the sham group, which became substantially attenuated by TNP-ATP. P2X3 receptors expressed in DRG were significantly increased in both mRNA and protein levels after ovariectomy and then reversed after estrogen replacement, while a similar increase was not observed after orchiectomy in male rats. Furthermore, P2X3 mRNA was significantly decreased 24 h after the application of 17β-estradiol in a concentration-dependent manner in cultured DRG neurons. ICI 182,780, an estrogen receptor antagonist, blocked the reduction in the protein level. These results suggest that the female gonadal hormone, 17β-estradiol, might participate in the control of peripheral pain signal transduction by modulating P2X3 receptor-mediated events in primary sensory neurons, probably through genomic mechanisms.

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Acknowledgment

This study was supported by National Natural Science Foundation of China (NSFC, no. 30570597, B. Ma) and Program of Changjiang Scholar and innovative team. We are deeply grateful to Dr. Gillian E. Knight (from the Autonomic Neuroscience Centre, University College Medical School, UK) for her kind assistance in English writing.

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Authors and Affiliations

  1. Department of Physiology, Shanghai Second Military Medical University, Shanghai, 200433, People’s Republic of China

    Bei Ma, Li-hua Yu, Juan Fan, Binhai Cong, Ping He & Xin Ni

  2. Key Laboratory of Molecular Neurobiology, Ministry of Education, Second Military Medical University, Shanghai, 200433, People’s Republic of China

    Bei Ma & Xin Ni

  3. Autonomic Neuroscience Centre, University College Medical School, Royal Free Campus, Rowland Hill Street, London, NW3 2PF, UK

    Geoffrey Burnstock

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  1. Bei Ma
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  2. Li-hua Yu
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  3. Juan Fan
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  6. Xin Ni
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  7. Geoffrey Burnstock
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Correspondence to Bei Ma or Xin Ni.

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The first two authors contributed equally to this work.

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Ma, B., Yu, Lh., Fan, J. et al. Estrogen modulation of peripheral pain signal transduction: involvement of P2X3 receptors. Purinergic Signalling 7, 73–83 (2011). https://doi.org/10.1007/s11302-010-9212-9

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