title: Sigma-1 receptor antagonism restores injury-induced decrease of voltage-gated Ca2+ current in sensory neurons.
abstract: Sigma-1 receptor (σ1R), an endoplasmic reticulum-chaperone protein, can modulate painful response after peripheral nerve injury. We have demonstrated that voltage-gated calcium current is inhibited in axotomized sensory neurons. We examined whether σ1R contributes to the sensory dysfunction of voltage-gated calcium channel (VGCC) after peripheral nerve injury through electrophysiological approach in dissociated rat dorsal root ganglion (DRG) neurons. Animals received either skin incision (Control) or spinal nerve ligation (SNL). Both σ1R agonists, (+)pentazocine (PTZ) and DTG [1,3-di-(2-tolyl)guanidine], dose dependently inhibited calcium current (ICa) with Ba(2+) as charge carrier in control sensory neurons. The inhibitory effect of σ1R agonists on ICa was blocked by σ1R antagonist, BD1063 (1-[2-(3,4-dichlorophenyl)ethyl]-4-m​ethylpiperazine dihydrochloride) or BD1047 (N-[2-(3,4-dichlorophenyl)ethyl]-N-m​ethyl-2-(dimethylamino)ethylamine dihydrobromide). PTZ and DTG showed similar effect on ICa in axotomized fifth DRG neurons (SNL L5). Both PTZ and DTG shifted the voltage-dependent activation and steady-state inactivation of VGCC to the left and accelerated VGCC inactivation rate in both Control and axotomized L5 SNL DRG neurons. The σ1R antagonist, BD1063 (10 μM), increases ICa in SNL L5 neurons but had no effect on Control and noninjured fourth lumbar neurons in SNL rats. Together, the findings suggest that activation of σR1 decreases ICa in sensory neurons and may play a pivotal role in pain generation.
authors.affiliation: Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin (B.P., Y.G., W.-M.K., Q.H., H.-e.W.); and Department of Anesthesiology, Zablocki Veterans Affairs Medical Center, Milwaukee, Wisconsin (Q.H.).
authors.forename: Bin
authors.initials: B
authors.lastname: Pan
authors.affiliation: Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin (B.P., Y.G., W.-M.K., Q.H., H.-e.W.); and Department of Anesthesiology, Zablocki Veterans Affairs Medical Center, Milwaukee, Wisconsin (Q.H.).
authors.forename: Yuan
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin (B.P., Y.G., W.-M.K., Q.H., H.-e.W.); and Department of Anesthesiology, Zablocki Veterans Affairs Medical Center, Milwaukee, Wisconsin (Q.H.).
authors.forename: Wai-Meng
authors.initials: WM
authors.lastname: Kwok
authors.affiliation: Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin (B.P., Y.G., W.-M.K., Q.H., H.-e.W.); and Department of Anesthesiology, Zablocki Veterans Affairs Medical Center, Milwaukee, Wisconsin (Q.H.).
authors.forename: Quinn
authors.initials: Q
authors.lastname: Hogan
authors.affiliation: Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin (B.P., Y.G., W.-M.K., Q.H., H.-e.W.); and Department of Anesthesiology, Zablocki Veterans Affairs Medical Center, Milwaukee, Wisconsin (Q.H.) hwu@mcw.edu.
authors.forename: Hsiang-en
authors.initials: HE
authors.lastname: Wu
mesh_terms: D000818:Animals; D015220:Calcium Channels / Q000502:physiology*; D005029:Ethylenediamines / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000502:physiology; D008297:Male; D059348:Peripheral Nerve Injuries / Q000188:drug therapy* / Q000503:physiopathology; D024681:Potassium Channels, Calcium-Activated / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017480:Receptors, sigma / Q000037:antagonists & inhibitors* / Q000502:physiology; D011984:Sensory Receptor Cells / Q000502:physiology*; D000097605:Sigma-1 Receptor
chemical_list: D015220:Calcium Channels; D005029:Ethylenediamines; D024681:Potassium Channels, Calcium-Activated; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C097963:N-(2-(3,4-Dichlorphenyl)ethyl)-N,N',N'-trimethyl-1,2-ethandiamin