title: Thalamic neuron hyperexcitability and enlarged receptive fields in the STZ model of diabetic pain.
abstract: Distal limb pain in diabetes mellitus is frequently attributed to hyperexcitability of primary afferents associated with peripheral neuropathy. However, prior studies have demonstrated that, after traumatic nerve injury, hyperexcitability develops not only within primary afferents but also within pain-signalling neurons of the spinal cord dorsal horn and thalamic ventral posterolateral (VPL) nucleus, establishing a basis for tiered central pain generators or amplifiers. In this study we asked whether hyperexcitability develops within thalamic neurons in experimental painful diabetes. Diabetes was induced in adult male Sprague-Dawley rats with streptozotocin (STZ). Behavioral testing for tactile allodynia, performed one week prior to STZ injection and weekly thereafter, indicated that, by six weeks after STZ injection, mechanical allodynia had developed (mechanical withdrawal threshold <4 g, STZ; 21.75 g, control). Thalamic unit recordings were obtained from the VPL nucleus at seven weeks after STZ injection, in rats that met a criterion withdrawal threshold of <4 g, at a time when mean glucose level for control rats was 104.8+/-2.9, and for diabetic rats was 420.1+/-42.0. Our analysis shows that, in this model of diabetic neuropathic pain, thalamic VPL neurons develop hyperexcitability, with increased responses to phasic brush, press, and pinch stimuli applied to identified peripheral receptive fields. VPL neurons from diabetic rats also display enhanced spontaneous activity, independent of ascending afferent barrage, and enlarged receptive fields. These results suggest that aberrant levels of spontaneous activity and hyper-responsiveness of VPL thalamic neurons may contribute to diabetic neuropathic pain.
authors.affiliation: Department of Neurology, Yale University School of Medicine, New Haven, CT 06510, USA; Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, CT 06510, USA; Rehabilitation Research Center, Veterans Administration Connecticut Healthcare System, West Haven, CT 06516, USA. Electronic address: tanya.fischer@yale.edu.
authors.forename: Tanya Z
authors.initials: TZ
authors.lastname: Fischer
authors.affiliation: Department of Neurology, Yale University School of Medicine, New Haven, CT 06510, USA; Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, CT 06510, USA; Rehabilitation Research Center, Veterans Administration Connecticut Healthcare System, West Haven, CT 06516, USA. Electronic address: andrew.tan@yale.edu.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Tan
authors.affiliation: Department of Neurology, Yale University School of Medicine, New Haven, CT 06510, USA; Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, CT 06510, USA; Rehabilitation Research Center, Veterans Administration Connecticut Healthcare System, West Haven, CT 06516, USA. Electronic address: stephen.waxman@yale.edu.
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Waxman
mesh_terms: D000200:Action Potentials; D000704:Analysis of Variance; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D006943:Hyperglycemia / Q000503:physiopathology; D008297:Male; D008839:Microelectrodes; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D010146:Pain / Q000139:chemically induced / Q000503:physiopathology*; D010147:Pain Measurement; D010812:Physical Stimulation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013311:Streptozocin; D013788:Thalamus / Q000187:drug effects / Q000503:physiopathology*
chemical_list: D001786:Blood Glucose; D013311:Streptozocin