Nerve injury and neuropathic pain - A question of age

Maria Fitzgerald, Rebecca McKelvey, Maria Fitzgerald, Rebecca McKelvey

Abstract

The effects of peripheral nerve injury on somatosensory processing and pain are highly dependent upon the age at which the damage occurs. Adult nerve injury rapidly triggers neuropathic pain, but this is not so if the same nerve injury is performed in animals below postnatal day (P) 28, consistent with observations in paediatric patients. However, longitudinal studies show that pain hypersensitivity emerges later in life, when the animal reaches adolescence, an observation that could be of clinical importance. Here we discuss the evidence that the central consequences of nerve damage are critically determined by the status of neuroimmune regulation at different ages. In the first postnatal weeks, when spinal somatosensory circuits are undergoing synaptic reorganisation, the 'default' neuroimmune response is skewed in an anti-inflammatory direction, suppressing the excitation of dorsal horn neurons and preventing the onset of neuropathic pain. As animals grow up and the central nervous system matures, the neuroimmune profile shifts in a pro-inflammatory direction, unmasking a 'latent' pain response to an earlier nerve injury. The data predicts that nerve injury in infancy and childhood could go unnoticed at the time, but emerge as clinically 'unexplained' or 'functional' pain in adolescence.

Keywords: Adolescent; Anti-inflammatory; Dorsal horn; Microglia; Neonatal; Neuroimmune; Neuropathic pain; Paediatric; Peripheral nerve; Plasticity; Pro-inflammatory; Somatosensory.

Copyright © 2015. Published by Elsevier Inc.

Figures

Fig. 1
Fig. 1
The dorsal horn response to peripheral nerve injury depends upon age. A model is proposed above of the cellular activity in the dorsal horn following nerve injury at different time points and postnatal stages Top: Neonatal (day 1–7) nerve injury results in primary afferent sprouting, and there is no pain behaviour. It is proposed that microglia are phagocytic (blue cells) and resident T helper cells (pink circular cells) are predominantly type Th2, that is anti-inflammatory. This cellular environment promotes and supports structural plasticity and postnatal neuronal circuit development (dark red neurons). Centre: Juvenile (day 10) nerve injury initially triggers an anti-inflammatory response in the dorsal horn with anti-inflammatory T helper cell activity (Th2) and microglial activity (M2) associated with release of cytokines such as IL4 and IL10. There is no pain behaviour. Bottom: Juvenile (day 10) nerve injury causes a later, delayed onset pro-inflammatory response in the dorsal horn. This arises from a switch of microglial and T cell activity from M2 and Th2 to M1 and Th1, associated with the release of pro-inflammatory cytokines such as IL1, TNF and the neurotrophin, BDNF. These, in turn, excite dorsal horn neurons and as a result trigger pain behaviour.

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