Targeting of CaV3.2 T-type calcium channels in peripheral sensory neurons for the treatment of painful diabetic neuropathy.
Pain-sensing sensory neurons (nociceptors) of the dorsal root ganglion (DRG) can become sensitized (hyperexcitable) in response to pathological conditions such as diabetes, which in turn may lead to the development of painful peripheral diabetic neuropathy (PDN). Because of insufficient knowledge about the mechanisms for this hypersensitization, current treatment for painful PDN has been limited to somewhat nonspecific systemic drugs having significant side effects or potential for abuse. Recent studies have established that the CaV3.2 isoform of T-channels makes a previously unrecognized contribution to sensitization of pain responses by enhancing excitability of nociceptors in animal models of type 1 and type 2 PDN. Furthermore, it has been reported that the glycosylation inhibitor neuraminidase can inhibit the native and recombinant CaV3.2 T-currents in vitro and completely reverse mechanical and thermal hyperalgesia in diabetic animals with PDN in vivo. Understanding details of posttranslational regulation of nociceptive channel activity via glycosylation may facilitate development of novel therapies for treatment of painful PDN. Pharmacological targeting the specific pathogenic mechanism rather than the channel per se may cause fewer side effects and reduce the potential for drug abuse in patients with diabetes.
Departments of Anesthesiology and Neuroscience, University of Virginia School of Medicine, Mail Box 800710, Charlottesville, VA, 22908-0710, USA, st9d@virginia.edu.
Slobodan M
SM
Todorovic
Vesna
V
Jevtovic-Todorovic
D000818:Animals; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000378:metabolism*; D020747:Calcium Channels, T-Type / Q000378:metabolism*; D003929:Diabetic Neuropathies / Q000188:drug therapy / Q000378:metabolism*; D016503:Drug Delivery Systems / Q000639:trends*; D006801:Humans; D010146:Pain / Q000188:drug therapy / Q000378:metabolism*; D010525:Peripheral Nerves / Q000187:drug effects / Q000378:metabolism; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000378:metabolism*; D016896:Treatment Outcome
C479952:CACNA1H protein, human; D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type