No abstract

The response to tissue injury includes sensitization of peripheral nociceptors and central neuronal pathways leading to acute clinical and inflammatory pain. A further response is sprouting of sensory nerve terminals in the region of skin damage. This hyperinnervation response is particularly intense in neonates compared with adults. In this study, we tested the effect of regional nerve block at the time of injury on skin hyperinnervation. Anaesthetized newborn rat pups were treated with percutaneous sciatic nerve block injections of 0.25% bupivacaine 25 microliters followed by a localized hindpaw skin wound. Cutaneous innervation was studied by image analysis of immunostained skin sections, 7 days after wounding, and sensory thresholds were assessed using von Frey hairs. The results showed that both hyperinnervation and hypersensitivity were not significantly altered by the application of a regional nerve block at the time of injury. This suggests that regional analgesia, used commonly in clinical practice, is unlikely to prevent the hyperinnervation that follows skin wounding.

The mechanisms for directing and organising sensory axons within developing skin remain largely unknown. The present study provides the first evidence that signalling occurs between A-ephrins and Eph-A receptors during the development of rat cutaneous sensory innervation both during normal development and following skin injury. Specifically, our data indicate that ephrin-A4 mRNA and protein are expressed in the epidermis during late embryogenesis and the early postnatal period (E16-P3), and expression is significantly down-regulated postnatally. In addition, Eph-A receptors are expressed on dorsal root ganglia (DRG) cells at birth. The pattern of ephrin-A4 expression is mirrored by epidermal innervation, so that sensory terminals are restricted to epidermal regions devoid of ephrin-A4 but increase as ephrin-A4 expression subsides postnatally. Neonatal skin wounding causes sensory hyperinnervation and a differential screen of wounded vs. nonwounded skin revealed down-regulation of epidermal ephrin-A4 following neonatal skin wounding. Expression studies showed that this down-regulation is below the wound and coincides exactly with the onset of hyperinnervation. In vitro experiments show a function for ephrin-A4-Fc in inhibiting rat DRG neuronal growth and guidance when presented as either substratum-bound stripes of ephrin-A4-Fc or as soluble clustered proteins. In conclusion, these observations suggest that the Eph family ligand ephrin-A4 has an inhibitory influence on neonatal cutaneous nerve terminals from DRG sensory neurons in the hindlimb, and may serve to prevent inappropriate innervation of cutaneous regions. In addition, the absence of ephrin-A4 following neonatal skin wounding may play a critical permissive role in the sprouting response.

TOC summaryNewborn skin wounding causes an upregulation of NT-3 and cutaneous sensory hyperinnervation that contributes to the increased pain and sensitivity associated with wounding.

The pathways, synapses and molecules involved in pain processing in the newborn are not only required to trigger repair and recuperation but are also involved in the process of forming a mature nervous system. Sensory neurons in the dorsal root ganglion and dorsal horn express a phenomenal array of molecules which contribute to their structural and functional characteristics and many of these are developmentally regulated both pre- and postnatally. In order to understand nociceptive signalling and pain in the neonate we need a clear picture of that regulation. This review concentrates on the changing expression of selected key molecules, receptors and channels in the embryo, neonate and adult, which both characterise the sensory neuron and contribute to its response to painful stimuli in normal and pathological conditions.