Long‐term sensory hyperinnervation following neonatal skin wounds

Abstract

Skin innervation during wound healing was investigated using immunocytochemical staining with the panneuronal marker antiprotein gene product (PGP) 9.5, which labels the entire innervation of the skin throughout development and in the adult. Full-thickness skin wounds in the hairy skin of the foot in neonatal rats result in pronounced hyperinnervation of the tissue that persists long after the wound has healed (at least 12 weeks). Quantification of this hyperinnervation by image analysis indicates that skin innervation density in the wounded area can increase up to 300%. The effect is greatest when wounds are performed at postnatal day (P) 0 or 7, declining when performed at P14 and P21 to resemble the weaker and transient effect in the adult. Staining with selective markers for different neuronal populations innervating skin (monoclonal anti-RT97 staining the myelinated axons of large light sensory ganglion cells; anticalcitonin gene-related peptide staining unmyelinated C axons, thinly myelinated A delta axons, and a subpopulation of large A fibres) reveal that both A- and C-fibre sensory axons contribute to this response. Destruction of the majority of the C-fibre population with neonatal capsaicin pretreatment, which leaves large A fibres intact, significantly reduces the hyperinnervation response at 14 days, confirming a major contribution from both A and C fibres. Sympathetic axons, stained with anti-tyrosine hydroxylase, do not sprout into the wounded area. Furthermore, pretreatment of neonates with 6-hydroxydopamine, which destroys the sympathetic innervation, does not significantly reduce the overall sprouting response, as identified by anti-PGP9.5 staining. Behavioural sensory testing revealed a 50% drop in the mechanical threshold in the wounded area after 3 weeks. These remarkably long-term and specific effects on sensory terminal axons following neonatal skin wounding indicate the plasticity of cutaneous innervation density following alterations in the target tissue at a critical stage of development.

Are There Long-Term Consequences of Pain in Newborn or Very Young Infants?

“…For example, full-thickness skin wounding of the hind paw during the first 21 postnatal days was shown to result in local hyperinnervation associated with healing of the wound such that the number and density of cutaneous axons was significantly increased, remarkably so when pups were wounded before postnatal day 7. At three weeks after pups were wounded on postnatal day 0, the mechanical flexion reflex threshold remained markedly lower compared to nonwounded animals, indicating long-lasting local hypersensitivity to pain (Reynolds & Fitzgerald, 1995). Recently, plantar skin wounding on the day of birth was shown to enlarge the organization of receptive fields in the dorsal horn assessed in the young adult rat, which is consistent with observations of long-lasting behavioral indicators of hypersensitivity to pain (Torsney & Fitzgerald, 2003).…”

Long-Term Behavioral Effects of Repetitive Pain in Neonatal Rat Pups

“…Peripheral mechanisms include the hyperinnervation and low pain thresholds noted following skin wounds in the neonatal period compared to similar wounds applied at older ages (P7, P14) or during adult life (50). Noxious stimulation in this study occurred during a critical period of postnatal development in the dorsal horn of the spinal cord (44).…”

Sympathetic hyperinnervation and inflammatory cell NGF synthesis following myocardial infarction in rats

“…As the wound heals, numbers of inflammatory cells diminish in concert with formation of a stable scar (Hasan, et al, 2000). In addition, both cutaneous wounds and myocardial infarction display peri-wound hyperinnervation (Reynolds and Fitzgerald, 1995;Liu, et al, 1999), suggesting that this is a common feature associated with inflammatory cell proliferation during wound healing. However, cutaneous wounds exhibit hyperinnervation by sensory nociceptor CGRPir axons whereas sympathetic nerves avoid the wound (Reynolds and Fitzgerald, 1995;Liu, et al, 1999).…”

“…In addition, both cutaneous wounds and myocardial infarction display peri-wound hyperinnervation (Reynolds and Fitzgerald, 1995;Liu, et al, 1999), suggesting that this is a common feature associated with inflammatory cell proliferation during wound healing. However, cutaneous wounds exhibit hyperinnervation by sensory nociceptor CGRPir axons whereas sympathetic nerves avoid the wound (Reynolds and Fitzgerald, 1995;Liu, et al, 1999). In contrast, cardiac peri-infarct tissue is hyperinnervated by sympathetic nerves but sensory and parasympathetic axons are scarce.…”