The development of pain circuits and unique effects of neonatal injury

Abstract

Pain is a necessary sensation that prevents further tissue damage, but can be debilitating and detrimental in daily life under chronic conditions. Neuronal activity strongly regulates the maturation of the somatosensory system, and aberrant sensory input caused by injury or inflammation during critical periods of early postnatal development can have prolonged, detrimental effects on pain processing. This review will outline the maturation of neuronal circuits responsible for the transmission of nociceptive signals and the generation of pain sensation-involving peripheral sensory neurons, the spinal cord dorsal horn, and brain-in addition to the influences of the neuroimmune system on somatosensation. This summary will also highlight the unique effects of neonatal tissue injury on the maturation of these systems and subsequent consequences for adult somatosensation. Ultimately, this review emphasizes the need to account for age as an independent variable in basic and clinical pain research, and importantly, to consider the distinct qualities of the pediatric population when designing novel strategies for pain management.

Keywords: Development; Inflammation; Injury; Maturation; Neonatal; Nociception; Pain.

Fig. 1. Innervation patterns of distinct sensory neuron classes during postnatal development.

Illustration of the stages of primary afferent innervation to the SCDH. A fibers innervate the gray matter first. The A fibers initially overshoot their final synaptic destinations and innervate laminae I-IV (top), and then gradually withdraw their axons to laminae III-IV during the first three postnatal weeks in rats—depicted on the bottom at P25 (Fitzgerald et al. 1994; Nakatsuka et al. 2000; Park et al. 1999). C fiber innervation begins after A fibers, but C fibers synapse in their appropriate adult destinations in lamina I and II from the beginning as shown on the bottom at P25 (Benn et al. 2001).

Fig. 2. RVM modulation of nociception develops postnatally and is shaped by neonatal injury.

The RVM area of the brainstem is a source of descending modulation onto nociceptive circuits in the spinal cord. The RVM is primarily pro-nociceptive during early development (left), both inhibits and facilitates nociception in adulthood (middle), but only inhibits nociception in adulthood after neonatal injury as shown on the right (Hathway et al. 2009; Walker et al. 2009).