Neuropathic Pain Is Constitutively Suppressed in Early Life by Anti-Inflammatory Neuroimmune Regulation

Abstract

Peripheral nerve injury can trigger neuropathic pain in adults but not in infants; indeed, for unknown reasons, neuropathic pain is rare before adolescence. We show here that the absence of neuropathic pain response in infant male rats and mice following nerve injury is due to an active, constitutive immune suppression of dorsal horn pain activity. In contrast to adult nerve injury, which triggers a proinflammatory immune response in the spinal dorsal horn, infant nerve injury triggers an anti-inflammatory immune response, characterized by significant increases in IL-4 and IL-10. This immediate anti-inflammatory response can also be evoked by direct C-fiber nerve stimulation in infant, but not adult, mice. Blockade of the anti-inflammatory activity with intrathecal anti-IL10 unmasks neuropathic pain behavior in infant nerve injured mice, showing that pain hypersensitivity in young mice is actively suppressed by a dominant anti-inflammatory neuroimmune response. As infant nerve injured mice reach adolescence (postnatal day 25-30), the dorsal horn immune profile switches from an anti-inflammatory to a proinflammatory response characterized by significant increases in TNF and BDNF, and this is accompanied by a late onset neuropathic pain behavior and increased dorsal horn cell sensitivity to cutaneous mechanical and cold stimuli. These findings show that neuropathic pain following early life nerve injury is not absent but suppressed by neuroimmune activity and that "latent" pain can still emerge at adolescence, when the neuroimmune profile changes. The data may explain why neuropathic pain is rare in young children and also why it can emerge, for no observable reason, in adolescent patients.

Subliminal (latent) processing of pain and its evolution to conscious awareness

“…The data show that while an interim protective process (lymphocytes) may be in place, changes are induced that remains subclinical until later in life. The data support the notion of development or presence of altered neural systems that manifest later “ emerge clinically as ‘ unexplained ’ pain ” later in life (Fitzgerald and McKelvey, 2016a; Vega-Avelaira et al, 2012) because it is suppressed (McKelvey et al, 2015). …”

Exposure to early life pain: long term consequences and contributing mechanisms

“…Dysregulation of NF-κB is a known consequence of early life stress [62,63], and likely contributes to the increased incidence of chronic pain syndromes [64] and anxiety disorders [20] observed in former NICU patients. Interestingly, mice subjected to nerve injury in the first postnatal week have increased spinal levels of the anti-inflammatory cytokines IL-4 and IL-10 [65], but as adults show increased spinal levels of the pro-inflammatory cytokine TNF that is associated with thermal and mechanical hyperalgesia [65]. This hypo-/hyper-sensitive immune profile is consistent with other adaptations observed as a result of early life pain, and clearly warrants additional investigation.…”

The impact of inflammation on respiratory plasticity

“…However, in other models of nociceptive sensitization, neonates exhibit a short-term protection from inflammatory nociceptive plasticity. Spared nerve injury (SNI), a model of neuropathic pain which induces spinal inflammation and hyperalgesia, has no effect on nociceptive sensitivity in mice and rats until 4-5 weeks of age due to central production of anti-inflammatory IL-10 (McKelvey et al, 2015). These studies exemplify the importance of age and cause of inflammation (endogenous – like SNI, or exogenous – like LPS) in determining the long-term effects of inflammation on the nervous system (Schwaller and Fitzgerald, 2014).…”