Previous studies of neuropathic pain caused by nerve injury have focused on the abnormal properties of the axotomized primary sensory neuron. A proportion of such neurons develop ectopic discharge that can originate at the site of the nerve injury or more proximally in the dorsal root ganglion. Surprisingly, myelinated but not unmyelinated injured afferents exhibit ectopic discharges following a spinal nerve lesion. This has led to the speculation that myelinated fibers acquire the capacity to sensitize central neurons. An alternative mechanism for neuropathic pain comes from studies in our laboratory and others in which ectopic discharges have been found in intact unmyelinated nociceptors that commingle with axotomized axons. This spontaneous activity in unmyelinated afferents may initiate/maintain sensitization of central neurons. Indeed, a number of lines of evidence from preclinical and clinical studies point to a role of uninjured cutaneous nociceptors in neuropathic pain. We propose to address three fundamental questions regarding the properties of these intact, hyperexcitable sensory neurons. First, what kinds of neurons are they? This is important, because some types, like mechanically-insensitive afferents (MIAs) or C-fibers from muscle are believed to have a particularly important role in initiating/maintaining central sensitization. Second, is the transduction mechanism normal in nociceptive afferents or has it become sensitized? Hyperalgesia and allodynia may be due, at least in part, to an enhanced response of primary afferents to natural stimuli. Third, how enduring are these changes in primary afferent neurons? This is important because chronic neuropathic pain could have different mechanisms than acute neuropathic pain. To address these questions, we will perform blinded electrophysiological experiments in a primate model of neuropathic pain. These studies will provide a biological rationale for the development of peripheral treatments for neuropathic pain. ? ? ?
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