Pain sensory neurons, or nociceptors, are particularly vulnerable to tissue trauma and inflammation during early life, and there is mounting evidence that peripheral inflammation in newborns can lead to permanent alterations in central nociceptive circuitry and pain-related behaviors. The extent to which these changes reflect permanent local alterations in the peripheral terminals of nociceptors is unknown, although such knowledge is critical to understanding causal mechanisms that either drive or help maintain altered nociceptive functioning in adults. Our recent work in neonatal mice has shown that the peripheral terminals of myelinated nociceptors undergo dramatic anatomical and physiological alterations within days of an inflammatory insult;by contrast, other cutaneous nociceptors were largely unaffected, and thus effects on myelinated nociceptors may be key to understanding altered adult pain states following early tissue trauma. The proposed experiments will directly examine the potential for permanent changes in myelinated nociceptor terminals using an in vivo trigeminal preparation in adult mice. This new preparation confers the ability, for the first time, to label the peripheral terminals of physiologically identified skin sensory neurons in adult animals. The overall goals of these studies are to determine the morphological diversity of myelinated nociceptor terminals in the skin of normal adult animals, and whether peripheral inflammation in early neonatal life results in permanent alterations of these endings. Through intracellular recordings, neurons will be physiologically characterized using a comprehensive suite of natural skin stimuli and then labeled in their entirety through iontophoresis of Neurobiotin. The peripheral terminals of labeled neurons will be reconstructed in skin sections to allow direct confirmation of functional morphology of individual physiologically identified skin sensory neurons. Analyses in normal (i.e., naove) adults will provide a critical backdrop for analyzing potential changes in these endings following neonatal inflammation. Potential long-term alterations in peripheral endings will be examined in two different models of experimentally induced inflammation in facial skin of newborn mice;the long-term effects of neonatal adjuvant-induced and carrageenan-induced inflammation will be compared to analyze potential differences between persistent versus acute inflammatory states in producing permanent alterations in myelinated nociceptor terminals. These results will be compared with the effects of experimentally induced inflammation in adulthood to determine whether the peripheral terminals of myelinated nociceptors retain the ability to respond to adult tissue trauma and therefore remain plastic throughout life. The results of these studies will provide an unprecedented understanding of the early maturation of this vital component of the pain system and the susceptibility of these afferents to early perturbation. This information will be pivotal to the development of future strategies in pediatric pain management and the translation of these strategies into effective practice.
There is mounting evidence that peripheral inflammation in newborns can lead to permanent alterations in pain circuitry and behaviors. The extent to which these permanent effects are driven by irreversible effects of early inflammation on the terminals of pain-sensing, or nociceptive sensory neurons in the skin is unknown. The proposed work will determine the morphological diversity of nociceptor terminals in the skin of normal adult mice, and determine whether early inflammation leads to in permanent alterations in these endings.
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