CaV3.2 T-type calcium channels in peripheral sensory neurons are important for mibefradil-induced reversal of hyperalgesia and allodynia in rats with painful diabetic neuropathy.
We recently showed that streptozotocin (STZ) injections in rats lead to the development of painful peripheral diabetic neuropathy (PDN) accompanied by enhancement of CaV3.2 T-type calcium currents (T-currents) and hyperexcitability in dorsal root ganglion (DRG) neurons. Here we used the classical peripherally acting T-channel blocker mibefradil to examine the role of CaV3.2 T-channels as pharmacological targets for treatment of painful PDN. When administered intraperitoneally (i.p.), at clinically relevant doses, mibefradil effectively alleviated heat, cold and mechanical hypersensitivities in STZ-treated diabetic rats in a dose-dependent manner. We also found that CaV3.2 antisense (AS)-treated diabetic rats exhibit a significant decrease in painful PDN compared with mismatch antisense (MIS)-treated diabetic rats. Co-treatment with mibefradil (9 mg/kg i.p.) resulted in reversal of heat, cold and mechanical hypersensitivity in MIS-treated but not in AS-treated diabetic rats, suggesting that mibefradil and CaV3.2 AS share the same cellular target. Using patch-clamp recordings from acutely dissociated DRG neurons, we demonstrated that mibefradil similarly blocked T-currents in diabetic and healthy rats in a voltage-dependent manner by stabilizing inactive states of T-channels. We conclude that antihyperalgesic and antiallodynic effects of mibefradil in PDN are at least partly mediated by inhibition of CaV3.2 channels in peripheral nociceptors. Hence, peripherally acting voltage-dependent T-channel blockers could be very useful in the treatment of painful symptoms of PDN.
Department of Anesthesiology, University of Virginia Health System, Charlottesville, Virginia, United States of America; Department of Physiology, Faculty of Pharmacy University of Belgrade, Belgrade, Serbia.
Aleksandar Lj
ALj
Obradovic
Department of Anesthesiology, University of Virginia Health System, Charlottesville, Virginia, United States of America; Department of Anesthesiology and Pain Medicine, Chuncheon Sacred Heart Hospital, College of Medicine, Hallym University, Chuncheon, South Korea.
Sung Mi
SM
Hwang
Department of Anesthesiology, University of Virginia Health System, Charlottesville, Virginia, United States of America.
Joseph
J
Scarpa
Department of Anesthesiology, University of Virginia Health System, Charlottesville, Virginia, United States of America; Department of Anesthesiology and Pain Medicine, Kangdong Sacred Heart Hospital, College of Medicine, Hallym University, Seoul, South Korea.
Sung Jun
SJ
Hong
Department of Anesthesiology, University of Virginia Health System, Charlottesville, Virginia, United States of America; Department of Neuroscience, University of Virginia Health System, Charlottesville, Virginia, United States of America; Neuroscience Graduate Program, University of Virginia Health System, Charlottesville, Virginia, United States of America.
Slobodan M
SM
Todorovic
Department of Anesthesiology, University of Virginia Health System, Charlottesville, Virginia, United States of America; Department of Neuroscience, University of Virginia Health System, Charlottesville, Virginia, United States of America; Neuroscience Graduate Program, University of Virginia Health System, Charlottesville, Virginia, United States of America.
Vesna
V
Jevtovic-Todorovic
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use*; D020747:Calcium Channels, T-Type / Q000502:physiology*; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy; D003929:Diabetic Neuropathies / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D006930:Hyperalgesia / Q000517:prevention & control*; D020748:Mibefradil / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011984:Sensory Receptor Cells / Q000187:drug effects* / Q000378:metabolism*; D013311:Streptozocin
C509958:Cacna1h protein, rat; D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D020748:Mibefradil; D013311:Streptozocin