Sigma-1 receptor antagonism restores injury-induced decrease of voltage-gated Ca²⁺ current in sensory neurons

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 (/_Ca) with Ba²⁺ as charge carrier in control sensory neurons. The inhibitory effect of σ1R agonists on/_Ca was blocked by s1R antagonist, BD1063 (1-[2-(3,4-dichlorophenyl)ethyl]-4- methylpiperazine dihydrochloride) or BD1047 (N-[2-(3,4-dichlorophenyl)ethyl]-N- methyl-2-(dimethylamino)ethylamine dihydrobromide). PTZ and DTG showed similar effect on/_Ca 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/_Ca 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/_Ca in sensory neurons and may play a pivotal role in pain generation.