That early postnatal experience may have long-term repercussions has been demonstrated for visual, auditory, tactile and chemical sensory systems. Multiple studies employing abnormal stimulation of these systems shortly after birth revealed significant alterations in their functionality in the adult individuals. These studies also pointed to three types of most-frequently observed early experience-induced alterations in the sensory circuitry which are likely to underlie the aberrations in the functionality of sensory systems in animals subjected to abnormal early experience; (i) alterations in connectivity of the neuronal processes, detectable as changes in the density and distribution of projecting sensory fibers; (ii) alterations in neurochemical organization of the circuitry, detectable as changes in the density and distribution of specific neurotransmitter and receptor-expressing cells as well as modifications in the levels of expression of neurotransmitters and receptors in the relevant centers of there central nervous system; and (iii) alterations in receptive field size and/or stimulus-response properties of neurons within the sensory circuit, detectable as changes in cells electrophysiological responses to appropriate sensory stimulation. Nociceptive circuitry undergoes significant postnatal maturation, and thus should also be vulnerable to modulations by early pain-associated experience. Indeed, recent studies demonstrated that exposure to pain-associated events early in life could induce long-term alterations in responses to pain by the affected individuals. Furthermore, experiments conducted in newborn rats have demonstrated that even a single local inflammation of a handpaw lasting for approximately 24 hours can result in significant changes in future withdrawal responses to noxious stimulation in the affected animals. However, the specific parameters of the """"""""window(s) of vulnerability"""""""" of the developing nociceptive circuitry to such short- lasting inflammation, as well as long-term changes in nociceptive circuitry underlying the altered nociceptive behaviors, have not been well investigated. It is unknown how global are the long term-effects produced by local inflammatory insult. Therefore, in this project: I. We will characterize the early postnatal sensitive period(s) of nociceptive circuitry to modulation by short-lasting inflammation; II. We will test the hypothesis that short-lasting early local inflammation is capable of inducing long-term alterations in morphological, biochemical and electrophysiological properties of the peripheral and spinal nociceptive circuitry serving the affected peripheral region (this specific aim will be performed in conjunction with Project 3, which focuses on the ability of early local inflammation to affect ion channels and electrophysiological properties in cells of the dorsal root ganglia); and III. Together with Projects 1 and 4, we will test the proposition that early local inflammatory insults may have a global long-term effect on nocifensive responses of the organism and that this global effect may be associated with alterations in the descending modulatory circuitry.
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