Molecular mechanisms of lipoic acid modulation of T-type calcium channels in pain pathway.
Alpha-lipoic acid (1,2-dithiolane-3-pentanoic acid; lipoic acid) is an endogenous compound used to treat pain disorders in humans, but its mechanisms of analgesic action are not well understood. Here, we show that lipoic acid selectively inhibited native Ca(V)3.2 T-type calcium currents (T-currents) and diminished T-channel-dependent cellular excitability in acutely isolated rat sensory neurons. Lipoic acid locally injected into peripheral receptive fields of pain-sensing sensory neurons (nociceptors) in vivo decreased sensitivity to noxious thermal and mechanical stimuli in wild-type but not Ca(V)3.2 knock-out mice. Ensuing molecular studies demonstrated that lipoic acid inhibited recombinant Ca(V)3.2 channels heterologously expressed in human embryonic kidney 293 cells by oxidating specific thiol residues on the cytoplasmic face of the channel. This study provides the first mechanistic demonstration of a nociceptive ion channel modulation that may contribute to the documented analgesic properties of lipoic acid in vivo.
Lee
Woo Yong
WY
Department of Anesthesiology and Pain Medicine InJe University, Sanggyepaik Hospital, Seoul 139-707, South Korea.
Orestes
Peihan
P
Latham
Janelle
J
Naik
Ajit K
AK
Nelson
Michael T
MT
Vitko
Iuliia
I
Perez-Reyes
Edward
E
Jevtovic-Todorovic
Vesna
V
Todorovic
Slobodan M
SM
D000595:Amino Acid Sequence; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D020747:Calcium Channels, T-Type / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009619:Nociceptors / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction; D010146:Pain / Q000188:drug therapy* / Q000378:metabolism; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D051381:Rats; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000378:metabolism; D008063:Thioctic Acid / Q000494:pharmacology* / Q000502:physiology*
D000700:Analgesics; C479952:CACNA1H protein, human; C504883:Cacna1h protein, mouse; C509958:Cacna1h protein, rat; D020747:Calcium Channels, T-Type; D008063:Thioctic Acid