Redox modulation of peripheral T-type Ca2+ channels in vivo: alteration of nerve injury-induced thermal hyperalgesia

Slobodan M Todorovic, Adam Meyenburg, Vesna Jevtovic-Todorovic
Pain 2004, 109 (3): 328-39
We reported recently that redox agents, including the endogenous amino acid L-cysteine, modulate T-type Ca2+ currents in primary sensory neurons in vitro, and alter mechanical and thermal nociception in peripheral nociceptors in vivo in intact animals [Neuron 31 (2001) 75]. Here, we studied the effects of locally applied redox agents (L-cysteine and 5,5'-dithio-bis-(2-nitrobenzoic acid) (DTNB) on thermal hyperalgesia in animals with neuropathic pain due to chronic constrictive injury (CCI) of the sciatic nerve. We found that, following injection into the peripheral receptive fields, the endogenous reducing agent L-cysteine increased thermal hyperalgesia in a dose-dependent manner in rats with CCI of the sciatic nerve as well as in sham-operated rats. However, the magnitude of the increase was smaller and duration of effect was shorter in rats with CCI of the sciatic nerve compared to sham-operated animals. DTNB, an exogenous oxidizing agent, induced dose-dependent alleviation of thermal hyperalgesia in rats with CCI of the sciatic nerve and caused analgesia in sham-operated rats. DTNB completely blocked L-cysteine-induced thermal hyperalgesia in both animal groups. Mibefradil, a potent and preferential T-type Ca2+ channel blocker, abolished L-cysteine-induced increase in thermal hyperalgesia in both animal groups suggesting the involvement of T-type Ca2+ channels in peripheral nociception. These results indicate for the first time that redox modulation of T-type Ca2+ channels in rat peripheral nociceptors is operational in pain states caused by peripheral axonal injury. Since thermal hyperalgesia is a common symptom of axonal injury, locally applied oxidizing agents could be used as a novel treatment to ameliorate neuropathic pain.

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