Nonlinear Inverted-U Shaped Relationship Between Aging and Epidermal Innervation in the Rat Plantar Hind Paw: A Laser Scanning Confocal Microscopy Study

Sankaranarayanan Kaliappan, Donald A. Simone, Ratan K. Banik

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2 Scopus citations


The under-reporting of pain and atypical manifestations of painful syndromes within the elderly population have been well documented, however, the specific relationship between pain and aging remains ambiguous. Previous studies have reported degenerative changes in primary afferents with aging. In this study, we questioned whether there is any change in the density of primary afferent endings within the epidermis of aged animals. Rats were categorically assessed in 4 age groups, each representing a key developmental stage across their life span: juvenile (2 months), adult (7 months); aged (18 months), and senescent (24–26 months). The plantar hind paw skin was removed, post-fixed, cut, and immunostained for protein gene product 9.5 and type IV collagen. Rats in the adult aged groups had significantly increased epidermal nerve densities and total lengths of immunoreactive nerve fibers, compared with juvenile as well as senescent rats. However, the paw withdrawal thresholds to punctate mechanical stimulation progressively increased with age, and did not exhibit a clear relationship with epidermal innervation. We conclude a nonlinear, inverted-U shaped relationship between rat plantar epidermal nerve density with aging, which does not correlate with mechanically-induced paw withdrawal behaviors. Perspective: This article presents age-related decreased epidermal innervation in rat hind paw skin, which partly explains mechanisms underlying decreased pain sensitivity in aged subjects. The report may help clinicians to understand that any compromise of pain-sensing pathway can lead to under-reporting of pain, inadequate analgesia, and slower recovery from a painful condition.

Original languageEnglish (US)
Pages (from-to)1015-1023
Number of pages9
JournalJournal of Pain
Issue number9
StatePublished - Sep 2018

Bibliographical note

Funding Information:
This work was performed in and supported by the NJ Neuroscience Institute and Seton Hall University School of Graduate Medical Education , JFK Medical Center , Edison, NJ. This work was also supported in part by the American Federation for Aging Research and the National Institutes of Health grants AG030352 and AG030352-02S2 to R.K.B.

Publisher Copyright:
© 2018 The American Pain Society


  • Aging
  • Fisher-344
  • collagen
  • epidermal nerve
  • protein gene product 9.5
  • rat


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