In diabetes, the high prevalence, chronicity and crippling impact of sensory symptoms of neuropathic origin, such as parasthesias, spontaneous pains and hyperalgesias from skin and muscle, challenge the clinical scientist to update investigation of the pathophysiological bases of those anomalies. Basic scientific and clinical research have led, over the past decade, to discovery of abnormal peripheral and central neurophysiological mechanisms capable of inducing distressing sensations in neuropathy. There is also recent knowledge on processes which link sensory function with sympathetic nervous activity and also with sympathetic and nociceptor-mediated neurovascular control events. Such research has inspired the design of powerful new methods of investigation in humans: Among them are: *microneurography; intraneural microstimulation; measurement of biophysical factors that rectify nerve excitability; quantitate modality- specific psychophysical somatosensory tests; pharmacological and electrophysiologicaltests for sympathetic mediation of pain, and measurement of equivalents of neurogenic inflammation. Through applying a range of those methods we propose to investigate in patients with painful diabetic neuropathy the existence and mode of operation of newly recognized primary peripheral and secondary central abnormal sensory mechanisms which have been shown, by others and ourselves, to operate in neuropathic animals or in experimental human subjects. These include: *neurogenic inflammation and sensitization of pain receptors; abnormal biophysical rectification and ectopic electrical discharges in peripheral axons; central distribution of imbalanced afferent input; secondary breakdown and hyperexcitability of CNS circuits, and sympathetic mediation of sensory discharge. The contemporary medical paradigm on painful diabetic neuropathy is ready for a conceptual and methodological shift. The results anticipated from the present research plan would resteer current lines of investigation and management protocols for sensory dysfunction in diabetic neuropathy. Novel primary or secondary neuropathic mechanisms found to operate in general in diabetic neuropathy will be presented to scientists and to the industry as priorities for development of pharmacological or other treatment modalities. Individual patients will be spared therapies sometimes addressed at questionable mechanisms, and will be directed towards customized modalities of treatment.
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