Sensitized peripheral nociception in experimental diabetes of the rat

• Published in: Pain (Amsterdam) Vol. 151; no. 2; pp. 496 - 505
• Main Authors: Fuchs, D., Birklein, F., Reeh, P.W., Sauer, S.K.
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA Elsevier B.V 01.11.2010; Elsevier
• Subjects: Action Potentials - drug effects; Action Potentials - physiology; Animals; Behavior, Animal; Biological and medical sciences; Bradykinin; Bradykinin - pharmacology; Calcitonin Gene-Related Peptide - metabolism; Capsaicin - pharmacology; CGRP; Cutaneous nociceptor; Diabetes Mellitus, Experimental - chemically induced; Diabetes Mellitus, Experimental - complications; Diabetes Mellitus, Experimental - pathology; Dinoprostone - metabolism; Disease Models, Animal; Dose-Response Relationship, Drug; Fundamental and applied biological sciences. Psychology; Hyperalgesia; Hyperalgesia - etiology; In Vitro Techniques; Male; Medical sciences; Nerve Fibers - physiology; Nervous system (semeiology, syndromes); Nervous system as a whole; Neurology; Neuropeptide release; Nociceptors - physiology; Pain Measurement - methods; Pain Threshold - drug effects; Pain Threshold - physiology; Prostaglandin E2; Rats; Reaction Time - drug effects; Reaction Time - physiology; Sciatic Nerve - drug effects; Sciatic Nerve - metabolism; Skin - drug effects; Skin - metabolism; Somesthesis and somesthetic pathways (proprioception, exteroception, nociception); interoception; electrolocation. Sensory receptors; Streptozocin - adverse effects; Substance P - metabolism; Vertebrates: nervous system and sense organs; Neuropeptide release; Prostaglandin E2; Cutaneous nociceptor; CGRP; Bradykinin; Hyperalgesia; Rat; Neuropathy; Neuropeptide; Nociceptor; Eicosanoid; Streptozotocin; Release; Human; Nociception; Nervous system diseases; Substance P; Arachidonic acid derivatives; Rodentia; Calcitonin gene related peptide; Foot; Vertebrata; Mammalia; Skin; Tachykinin; Sciatic nerve
• ISSN: 0304-3959; 1872-6623
• DOI: 10.1016/j.pain.2010.08.010

Painful neuropathy is a common complication of diabetes. Particularly in the early stage of diabetic neuropathy, patients are characterized by burning feet, hyperalgesia to heat, and mechanical stimuli, as if residual nociceptors were sensitized. Such symptoms are barely explained by common pathophysiological concepts of diabetic neuropathy. Diabetes was induced in Wistar rats by streptozotocin (STZ). After 4weeks behavioral testing (Plantar test, Randall–Selitto) was conducted. Basal and stimulated release of calcitonin gene-related peptide (CGRP), Substance P (SP) and prostaglandin E2 (PGE2) from isolated skin and sciatic nerve were assessed by enzyme immunoassays. Electrophysiological properties of identified nociceptors under hyperglycemic, hypoxic, and acidotic conditions were investigated using the skin-nerve preparation. The diabetic rats showed hyperalgesia to heat and pressure stimulation. The basal CGRP/SP release was reduced, but chemical stimulation with bradykinin induced greater release of SP, CGRP and PGE2 than in control animals. In contrast, capsaicin-stimulated CGRP release was reduced in sciatic nerves. Hypoxia per se lowered von Frey thresholds of most C-nociceptors to half. Hyperglycemic hypoxia induced ongoing discharge in all diabetic but not control C-fibers which was further enhanced under acidosis. Sensory and neurosecretory nociceptor functions are sensitized in diabetes. Diabetic C-fibers show exaggerated sensitivity to hyperglycemic hypoxia with and without additional acidosis, conditions that are thought to mimic ischemic episodes in diabetic nerves. Ongoing C-fiber discharge is known to induce spinal sensitization. Together with altered receptor and ion channel expressions this may contribute to painful episodes in diabetic neuropathy.