| Popis: |
When we are born, our environment changes drastically, and our nervous system responds by continuously adapting and acclimating to the input it receives. After birth, the somatosensory system is immature and in a stage of being developed and refined, which likely contributes to the exaggerated mechanical sensitivity and lack of coordination in the reflex responses of neonates. Although substantial progress is being made in elucidating the neuronal networks transmitting specific somatosensory modalities and contributing to pain disorders, it is imperative to note that these findings cannot be generalized to pediatric populations due to the dynamic nature of the somatosensory system in the early postnatal period. The spinal dorsal horn (DH) is an area where incoming peripheral signals are processed and modulated by vast networks of interneurons before being transmitted to the brain by spinoparabrachial projection neurons in lamina I. Yet despite the current research efforts to map the function of these DH interneuron circuits, inhibitory mechanisms in the DH are known to be weaker in early life1, and require additional investigation in order to generalize findings in the adult to pediatric populations. The spinal dynorphin-expressing (DYN) interneuron circuit has been implicated in gating mechanosensation and itch in adult animals, therefore, in order to better understand its function throughout the lifespan, we used in vitro electrophysiology and discovered that DYN interneuron sensory afferent activation, intrinsic excitability, and inhibition of projection neurons was immature and less efficient in early life. The immature spinal DYN circuit may have eliminated the ability of these interneurons to inhibit itch in early life. However, we found that DYN interneuron-mediated inhibition of mechanical sensitivity remained intact throughout the lifespan, highlighting the importance of studying the unique developmental trajectories of modality-specific neurocircuit functions. Early postnatal development may represent a critical period of heightened plasticity when the somatosensory system is more susceptible to permanent alterations after tissue damage. Human and rodent data suggest that neonatal injury may predispose individuals for exacerbated pain after adult reinjury, and this is coupled with data in rodents demonstrating persistently reduced inhibitory mechanisms in the spinal DH after prior surgical or inflammatory injury in the neonatal period. We provide evidence that DYN interneurons are a specific population affected in the previously observed reduction in membrane excitability, sensory deinnervation, and diminished output of GABAergic interneurons after neonatal hindpaw incision. Furthermore, neonatal injury causes a widespread, sustained hypoalgesia in adulthood, which may be due to constitutively increased endogenous opioid influence. Although persistently heightened opioid signaling has been demonstrated in the periaqueductal grey region of the midbrain after neonatal inflammation, after neonatal hindpaw incision we found that DH projection neurons display a functional increase in inward-rectifying G protein coupled potassium channels (GIRKs), which are the downstream effectors of numerous metabotropic receptors—including µ opioid and GABAb. Taken together, these results collectively provide convincing evidence for the postnatal development of an identified spinal circuit—in addition to the persistent weakening of inhibitory mechanisms that may have implications in the modality-specific pathology following neonatal injury. |
