Modulation of Developing Spinal Nociceptive Circuits by Sensory Input

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Description (provided by applicant): The overall goal of the proposed research is to better comprehend the maturation of spinal pain networks in the neonate. It is now clear that knowledge of the environmental and genetic factors which influence the formation of nociceptive circuits in the central nervous system (CNS) is essential to improving the treatment of pain in children. Recent behavioral evidence suggests that sensory experience during the neonatal period regulates the maturation of central pain networks and can have long-term effects on pain processing. An understanding of how emergent central pain circuits are modulated by sensory input at the cellular level will yield crucial insights into the mechanisms underlying these persistent changes in pain sensitivity. Unfortunately, nothing is currently known about how the level of activity in primary sensory afferent pathways influences synaptic function in developing nociceptive circuits. Since the synaptic integration of nociceptive signals within the CNS begins in the superficial dorsal horn (SDH) of the spinal cord, a detailed characterization of how synaptic networks in the SDH are shaped by primary afferent input during the early postnatal period represents a logical and important first step towards addressing this issue. We hypothesize that excitatory synaptic function in the SDH is modulated by sensory input from the periphery during a critical period of postnatal development and that the effects of tissue injury on SDH synaptic networks are therefore highly age-dependent. This proposal will test this hypothesis by manipulating the level of activity in primary afferent pathways during the early postnatal period and subsequently characterizing the properties of glutamatergic synaptic signaling in the rat dorsal horn using electrophysiological, immunohistochemical and biochemical approaches. This will involve two specific aims: (1) To determine if the efficacy of glutamatergic synapses in the SDH of the rat spinal cord depends on the level of primary afferent input during a critical postnatal period; and (2) To determine whether the consequences of peripheral inflammation for synaptic function in the developing SDH depend on postnatal age. Since the intensive care treatment of infants often requires multiple invasive procedures which alter the normal pattern of somatosensory input to the spinal cord at a time when the immature nervous system is capable of significant plasticity, understanding how sensory experience affects synaptic development in the dorsal horn is necessary to fully realize the short and long-term consequences of these procedures for pain sensation. PUBLIC HEALTH RELEVANCE: It is now universally recognized that human infants can experience considerable pain as a result of disease, surgery or intensive care therapies. However, the clinical treatment of pain in adults cannot easily be translated to children, as it is clear that the immature nervous system is not merely a simplified version of the mature form but rather organized in a fundamentally different manner. Increasing our understanding of the maturation of pain systems at the cellular level will not only provide insight into the mechanisms of action of those analgesics already prescribed to children, but also aid in the design of novel analgesic strategies which are developmentally appropriate.