Effects of adrenergic stimulus on the activities of Ca2+ and K+ channels of dorsal root ganglion neurons in a neuropathic pain model.
We hypothesized that abnormal activity and adrenergic sensitivity in injured dorsal root ganglion (DRG) neurons are due to an intrinsic alteration of the cell body membrane. We investigated the effects of adrenergic stimulus on the activities of Ca2+ and K+ channels of DRG neurons in a rat chronic constriction injury (CCI) model. At first, we demonstrated thermal hyperalgesia and sprouting sympathetic nerve fibers in the ipsilateral L4-L5 DRGs. Using whole-cell patch clamp techniques, we found that alpha2-adrenergic stimulus by 10 microM norepinephrine (NE) inhibited inward currents (IBa, Ba2+ as a charge carrier) through voltage-dependent Ca2+ channels (VDCCs) of DRGs in the CCI model by 42%, whereas it enhanced the IBa by 18% in control animals. The inhibitory effect of NE disappeared by pretreatment with the N-type VDCC antagonist omega-conotoxin GVIA (1 microM). NE shifted the inactivation curve to a more negative potential, showing that it has inhibitory effects on IBa both in activated and in inactivated states. alpha2-Adrenergic stimulus also inhibited outward K+ currents by 24% in the CCI model, while it had no effect on the currents in control animals. The inhibitory effect of NE was blocked by pretreatment with the Ca2+-activated K+ (KCa) channel antagonist charybdotoxin (40 nM). The NE-induced inhibitory effects both on N-type VDCC and on KCa channels in injured DRG neurons of the CCI model could lead to cell membrane depolarization, resulting in a spontaneous discharge of action potential and an increase in sensitivity to adrenergic stimulus.
Honma
Y
Y
Department of Anesthesiology, Sapporo Medical University School of Medicine, South 1, West 16, Chuo-ku, Sapporo 060-8543, Japan.
Yamakage
M
M
Ninomiya
T
T
D000818:Animals; D001464:Barium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002462:Cell Membrane / Q000187:drug effects; D002478:Cells, Cultured; D003250:Constriction; D004195:Disease Models, Animal; D005727:Ganglia, Spinal / Q000187:drug effects* / Q000473:pathology; D008297:Male; D009412:Nerve Fibers / Q000187:drug effects; D009416:Nerve Regeneration; D009437:Neuralgia / Q000188:drug therapy* / Q000473:pathology; D009474:Neurons / Q000187:drug effects*; D009638:Norepinephrine / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers; D051381:Rats; D017208:Rats, Wistar
D002121:Calcium Channel Blockers; D026902:Potassium Channel Blockers; D001464:Barium; D009638:Norepinephrine