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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Article info
Publication history
Published online: February 23, 2021
Accepted:
February 7,
2021
Received in revised form:
January 27,
2021
Received:
September 18,
2020
Footnotes
This work was supported by the NIH grant AR063312.
The authors declare no conflicts of interest.
Identification
Copyright
© 2021 by United States Association for the Study of Pain, Inc.
