Peripheral Nerve Regeneration and Dorsal Horn Plasticity

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DESCRIPTION (provided by applicant): Peripheral nerve injury is a relatively common occurrence. Normally the damaged nerve regenerates to reinnervate peripheral tissues. This process results in significant plasticity in the somatosensory system. Immediately following reinnervation there is a loss of normal tactile acuity that often improves with time. These lesions can also result in other symptoms such as hypersensitivity, which can range from mild innocuous hyperalgesia to painful conditions including allodynia or causalgia that can persist, greatly affecting the individual's quality of life. It is believed that a major contribution to these pain syndromes involves the ectopic sprouting of sensory fibers normally signaling light touch, into the pain regions of the spinal cord. During the last funding period it was found that this sprouting does not occur, and in contrast to previous findings, that myelinated nociceptive fibers project extensively throughout the superficial dorsal horn. These findings suggest that myelinated nociceptors provide the observed novel fast conducting inputs to superficial dorsal horn cells previously thought to come from low-threshold fibers. The long-term goal of this proposal is to determine the contribution of myelinated nociceptors and their spinal connection to these chronic pain states. The proposed research will address three specific hypotheses: Hypothesis 1: Following peripheral nerve regeneration myelinated nociceptors exhibit increased sensitivity to mechanical and thermal stimulation. Hypothesis 2: Following peripheral nerve regeneration cells in the superficial dorsal horn exhibit an increased sensitivity to low threshold mechanoreceptive and thermal inputs, Hypothesis 3: Following peripheral nerve regeneration cells in the superficial dorsal horn receive increased functional inputs from myelinated nociceptors, but not from myelinated low threshold mechanoreceptors. These hypotheses will be tested using an ex vivo mouse spinal cord/skin/nerve preparation that allows the intracellular recording and characterization of cutaneous response properties of individual cutaneous sensory neurons and cells located in the superficial laminae of the spinal dorsal horn before, during and after nerve regeneration. Following their characterization individual cells are stained and histologically recovered to allow for further analysis at both the light and electron microscopic levels. This preparation also allows for the dual intracellular recording of individual identified sensory neurons and superficial dorsal horn cells. The individual nociceptive or non-nociceptive myelinated fibers can then be individually stimulated to determine synaptic linkage before and after regeneration. The results of these experiments will greatly increase our understanding of post nerve injury plasticity in the somatosensory system and possible reveal mechanisms that could contribute to persistent pain states that can accompany these injuries.