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Nociceptor Overexpression of NaV1.7 Contributes to Chronic Muscle Pain Induced by Early-Life Stress

  • Pedro Alvarez
    Affiliations
    Department of Oral and Maxillofacial Surgery, University of California, San Francisco, San Francisco, California
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  • Oliver Bogen
    Affiliations
    Department of Oral and Maxillofacial Surgery, University of California, San Francisco, San Francisco, California

    UCSF Pain and Addiction Research Center, University of California, San Francisco, San Francisco, California
    Search for articles by this author
  • Paul G. Green
    Affiliations
    Department of Oral and Maxillofacial Surgery, University of California, San Francisco, San Francisco, California

    UCSF Pain and Addiction Research Center, University of California, San Francisco, San Francisco, California

    Department of Preventative and Restorative Dental Sciences, University of California, San Francisco, San Francisco, California
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  • Jon D. Levine
    Correspondence
    Address reprint requests to Jon D. Levine, MD, PhD, University of California San Francisco, 513 Parnassus Ave., Room S709, San Francisco, CA 94143-0440.
    Affiliations
    Department of Oral and Maxillofacial Surgery, University of California, San Francisco, San Francisco, California

    UCSF Pain and Addiction Research Center, University of California, San Francisco, San Francisco, California

    Department of Medicine, University of California San Francisco, San Francisco, California
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Published:February 23, 2021DOI:https://doi.org/10.1016/j.jpain.2021.02.003

      Highlights

      • Early-life stress is a well-established risk factor for chronic muscle pain.
      • Rats submitted to limited bedding stress as neonates display muscle pain as adults.
      • Limited bedding rats exhibit increased nociceptor expression of NaV1.7 as adults.
      • Antisense knockdown and pharmacological inhibition of NaV1.7 attenuated muscle pain.
      • NaV1.7 is a potential therapeutic target for the treatment of chronic muscle pain.

      Abstract

      Adult rats previously submitted to neonatal limited bedding (NLB), a model of early-life stress, display muscle mechanical hyperalgesia and nociceptor hyperexcitability, the underlying mechanism for which is unknown. Since voltage-gated sodium channel subtype 7 (NaV1.7) contributes to mechanical hyperalgesia in several preclinical pain models and is critical for nociceptor excitability, we explored its role in the muscle hyperalgesia exhibited by adult NLB rats. Western blot analyses demonstrated increased NaV1.7 protein expression in L4-L5 dorsal root ganglia (DRG) from adult NLB rats, and antisense oligodeoxynucleotide (AS ODN) targeting NaV1.7 alpha subunit mRNA attenuated the expression of NaV1.7 in DRG extracts. While this AS ODN did not affect nociceptive threshold in normal rats it significantly attenuated hyperalgesia in NLB rats. The selective NaV1.7 activator OD1 produced dose-dependent mechanical hyperalgesia that was enhanced in NLB rats, whereas the NaV1.7 blocker ProTx-II prevented OD1-induced hyperalgesia in control rats and ongoing hyperalgesia in NLB rats. AS ODN knockdown of extracellular signal-regulated kinase 1/2, which enhances NaV1.7 function, also inhibited mechanical hyperalgesia in NLB rats. Our results support the hypothesis that overexpression of NaV1.7 in muscle nociceptors play a role in chronic muscle pain induced by early-life stress, suggesting that NaV1.7 is a target for the treatment of chronic muscle pain.

      Perspective

      We demonstrate that early-life adversity, induced by exposure to inconsistent maternal care, produces chronic muscle hyperalgesia, which depends, at least in part, on increased expression of NaV1.7 in nociceptors.

      Key words

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