Neuroimmune modulation of pain across the developmental spectrum

Abstract

Today's treatment for chronic pain is inadequate, and novel targets need to be identified. This requires a better understanding of the mechanisms involved in pain sensitization and chronification. In this review, we discuss how peripheral inflammation, as occurs during an infection, modulates the central pain system. In rodents, neonatal inflammation leads to increased pain sensitivity in adulthood by priming immune components both peripherally and centrally. The excitability of neurons in the spinal cord is also altered by neonatal inflammation and may add to pain sensitization later in life. In adult humans, inflammation modulates pain sensitivity as well, partly by affecting the activity in brain areas that process and regulate pain signals. Low-grade inflammation is common in clinical populations both peripherally and centrally, and priming of the immune system has also been suggested in some pain populations. The nociceptive and immune systems are primed by infections and inflammation. The early life programming of nociceptive responses following exposure to infections or inflammation will define individual differences in adult pain perception. Immune-to-brain mechanisms and neuroimmune pathway need further investigation as they may serve both as predictors and therapeutic targets in chronic pain.

Figure 1. Neonatal inflammation can sensitize the pain system for life.

Early life peripheral inflammation affects the development of pain pathways by several mechanisms that work in concert to sensitize the pain system. Immune components are primed in both the periphery and CNS in ways that promote increased pain processing at later stages of development, and increased nerve excitability within the dorsal horn of the spinal cord. Inflammation experienced early in life is thus one of the components that form and fine-tune the developing pain system. Figure is created using images from Servier Medical Art (http://smart.servier.com/).

Figure 2. Peripheral inflammation modulates the pain system throughout life.

The figure depicts a model that incorporates findings from rodent and human experimental inflammation models in different developmental stages. In this model, peripheral inflammation modulates pain processing from birth to adulthood. Early life inflammation impacts the development of an individual’s pain system via immunological and neuronal changes, that in turn define individual differences in neuroimmune communication later in life. A primed pain system is more susceptible to the detrimental effect of immune-to-brain signaling during illness or low-grade inflammation. Augmented periphery-to-CNS neuroimmune interaction may result in the development, maintenance and spreading of long-term pain, as well as in the development of comorbid syndromes that are commonly experienced by chronic pain patients. Figure is created using images from Servier Medical Art (http://smart.servier.com/).