Primary and secondary hyperalgesia can be differentiated by postnatal age and ERK activation in the spinal dorsal horn of the rat pup

Abstract

Noxious C-fibre stimulation produces increased sensitivity within the injured area (primary hyperalgesia), and a surrounding zone of secondary hyperalgesia. As significant changes in nociceptive processing occur during development, we compared C-fibre induced primary and secondary hyperalgesia in rat pups aged 3, 10 and 21 postnatal (P) days. Hyperalgesia was measured by electromyography flexion reflex recordings following mustard oil or capsaicin at the site of (primary hyperalgesia), or distant to (secondary hyperalgesia) hindpaw mechanical stimuli. Primary hyperalgesia was induced at all postnatal ages, whereas secondary hyperalgesia could not be demonstrated at P3 but was evident at P10 and P21. At P3, extracellular signal-regulated kinase (ERK) protein is present in the dorsal horn, but hindpaw capsaicin produced minimal ERK activation restricted to the fourth lumbar segment. At P21, capsaicin induced intense phosphoERK expression in the superficial dorsal horn throughout several lumbar segments, consistent with the spread of secondary hyperalgesia. Intrathecal administration of the MEK (ERK kinase) inhibitor PD98059 prevented mustard oil and capsaicin-induced secondary hyperalgesia at P21, but had no effect on primary hyperalgesia at P3 or P21. These results provide evidence that primary and secondary hyperalgesia are differentially modulated during development. Furthermore, since ERK activation is required for secondary hyperalgesia, phosphoERK expression can be used to map the spatial distribution of neuronal activation in the spinal cord. Understanding changing responses to injury in the developing nervous system is important for clinical paediatric practice, and will enhance our ability to target the most effective site with a developmentally appropriate analgesic regime.