Cell-specific alterations of T-type calcium current in painful diabetic neuropathy enhance excitability of sensory neurons.
Recent data indicate that T-type Ca2+ channels are amplifiers of peripheral pain signals, but their involvement in disorders of sensory neurons such as those associated with diabetes is poorly understood. To address this issue, we used a combination of behavioral, immunohistological, molecular, and electrophysiological studies in rats with streptozotocin (N-[methylnitrosocarbamoil]-D-glucosamine)-induced early diabetic neuropathy. We found that, in parallel with the development of diabetes-induced pain, T-type current density increased by twofold in medium-size cells from L4-L5 dorsal root ganglia (DRG) with a depolarizing shift in steady-state inactivation. This not only correlated closely with more prominent afterdepolarizing potentials (ADPs) but also increased cellular excitability manifested as a lower threshold for burst firing in diabetic than in control cells. T-type currents and ADPs were potently inhibited by nickel and enhanced by L-cysteine, suggesting that the Ca(V)3.2 T-type channel isoform was upregulated. Both control and diabetic DRG cells with ADPs stained positively for isolectin B4, but only diabetic cells responded robustly to capsaicin, suggesting enhanced nociceptive function. Because increased excitability of sensory neurons may result in such pathological perceptions of pain as hyperalgesia and allodynia, upregulation of T-type Ca2+ currents and enhanced Ca2+ entry into these cells could contribute to the development of symptoms in diabetic neuropathy.
Jagodic
Miljen M
MM
Department of Anesthesiology, University of Virginia Health System, Charlottesville, Virginia 22908, USA.
Pathirathna
Sriyani
S
Nelson
Michael T
MT
Mancuso
Stefani
S
Joksovic
Pavle M
PM
Rosenberg
Ethan R
ER
Bayliss
Douglas A
DA
Jevtovic-Todorovic
Vesna
V
Todorovic
Slobodan M
SM
D000200:Action Potentials / Q000502:physiology*; D000818:Animals; D020747:Calcium Channels, T-Type / Q000502:physiology*; D003929:Diabetic Neuropathies / Q000503:physiopathology*; D005260:Female; D009475:Neurons, Afferent / Q000502:physiology*; D010147:Pain Measurement / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley
D020747:Calcium Channels, T-Type