Nelson, M.T., Joksovic, P.M., Perez-Reyes, E. & Todorovic, S.M. The endogenous redox agent L-cysteine induces T-type Ca2+ channel-dependent sensitization of a novel subpopulation of rat peripheral nociceptors. J. Neurosci. 25, 8766-8775

Department of Anesthesiology, University of Virginia, Charlottesville, Virginia, United States
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 10/2005; 25(38):8766-75. DOI: 10.1523/JNEUROSCI.2527-05.2005
Source: PubMed


Recent studies have demonstrated a previously unrecognized contribution of T-type Ca2+ channels in peripheral sensory neurons to pain sensation (nociception). However, the cellular mechanisms underlying the functions of these channels in nociception are not known. Here, in both acutely dissociated and intact rat dorsal root ganglion neurons, we characterize a novel subpopulation of capsaicin- and isolectin B4-positive nociceptors that also expresses a high density of T-type Ca2+ currents. Using these "T-rich" cells as a model, we demonstrate that the endogenous reducing agent L-cysteine lowers the threshold for nociceptor excitability and induces burst firing by increasing the amplitude of T-type currents and shifting the gating parameters of T-type channels. These findings, which provide the first direct evidence of T-type Ca2+ channel involvement in the control of nociceptor excitability, suggest that endogenous T-type channel agonists may sensitize a unique subpopulation of peripheral nociceptors, consequently influencing pain processing under normal or pathological conditions.

Full-text preview

Available from:
  • Source
    • "T-type calcium channels are primarily found in scattered small and medium sized DRG neurons, whereas the extremely large neurons do not express these channels [18]. Recent studies indicate that T-type calcium channels play an important role in regulating cellular excitability [19] [20]. Several pharmacological blockers and modulators of T-type calcium channels can ease neuropathic pain in a chronic constriction injury model [21]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: A previous study showed that antitumor-analgesic peptide (AGAP), a novel recombinant polypeptide, which had been expressed in Escherichia coli, exhibits analgesic and antitumor effects in mice. In the present study, we investigated the underlying analgesic mechanism of AGAP. The effect of AGAP on voltage-gated calcium channels (VGCCs) was assessed in acutely isolated rat dorsal root ganglia (DRG) neurons using the whole-cell patch clamp technique. The results showed that AGAP potently inhibited VGCCs, especially high-voltage activated (HVA) calcium channels. AGAP inhibited HVA and T-type calcium currents in a dose-dependent manner, but had no significant effect on their dynamic functions in rat small-diameter DRG neurons. AGAP inhibited N- and L-type calcium currents at 78.2% and 57.3%, respectively. Thus, the present study demonstrates that AGAP affects calcium currents through the inhibition of N-, L- and T-type channels in DRG neurons, explaining the potential mechanisms of antinociception.
    Biochemical and Biophysical Research Communications 09/2014; 452(1). DOI:10.1016/j.bbrc.2014.08.051 · 2.30 Impact Factor
  • Source
    • "Acutely isolated DRG neurons DRG cells from adolescent rats were prepared as previously described (Todorovic et al. 1998; Nelson et al. 2005; Choe et al. 2011). For recording, cells were plated onto uncoated glass coverslips, placed in a culture dish, and perfused with external solution. "
    [Show abstract] [Hide abstract]
    ABSTRACT: T-type calcium channels (T-channels) play an important role in controlling excitability of nociceptors. We have previously shown that a synthetic series of 5β-reduced steroids induce a voltage-dependent blockade of T-currents in rat dorsal root ganglia (DRG) cells in vitro and induce potent analgesia to thermal stimuli in rats in vivo (Mol Pharmacol 66:1223-1235, 2004). Here, we investigated the effects of the endogenous 5β-reduced neuroactive steroid molecule, epipregnanolone [(3β,5β)-3-hydroxypregnan-20-one], on peripheral nociception. We used acutely dissociated DRG cells in vitro from adult rats as well as in vivo pain studies in mice and rats to investigate the effects of epipregnanolone on DRG T-channels. We found that epipregnanolone reversibly blocked DRG T-currents with a half-maximal inhibitory concentration (IC50) of 2 μM and stabilized the channel in the inactive state. However, sodium, potassium, and gamma-aminobutyric acid (GABA)-gated ionic currents were not sensitive to the blocking effects of epipregnanolone even at 10 μM. In ensuing in vivo studies, we found that intraplantar ( injections of epipregnanolone directly into peripheral receptive fields reduced responses to nociceptive heat stimuli in rats in a dose-dependent fashion. Furthermore, epipregnanolone injections effectively reduced responses to peripheral nociceptive thermal and mechanical stimuli in wild-type mice but had no effect on the responses of CaV3.2 knockout mice. We conclude that the inhibition of peripheral CaV3.2 T-channels contributes to the potent analgesic effect of the endogenous steroid epipregnanolone.
    Psychopharmacology 05/2014; 231(17). DOI:10.1007/s00213-014-3588-0 · 3.88 Impact Factor
  • Source
    • "Functional expression of different Cav3 channels may influence Ca2+ signaling associated with different neuronal activities due to specific biophysical properties of these channels. Cav3.2 channels were shown to be underlying after depolarization potentials and participating in rebound discharge in medium [25] and T-rich [49] DRG neurons. However, relatively fast inactivation and slow recovery from inactivation limit the ability of Cav3.2 channels to respond to high frequency stimulation (>20 Hz). "
    [Show abstract] [Hide abstract]
    ABSTRACT: T-type Ca(2+) channels are known as important participants of nociception and their remodeling contributes to diabetes-induced alterations of pain sensation. In this work we have established that about 30% of rat nonpeptidergic thermal C-type nociceptive (NTCN) neurons of segments L4-L6 express a slow T-type Ca(2+) current (T-current) while a fast T-current is expressed in the other 70% of these neurons. Streptozotocin-induced diabetes in young rats resulted in thermal hyperalgesia, hypoalgesia, or normalgesia 5-6 weeks after the induction. Our results show that NTCN neurons obtained from hyperalgesic animals do not express the slow T-current. Meanwhile, the fraction of neurons expressing the slow T-current did not significantly change in the hypo- and normalgesic diabetic groups. Moreover, the peak current density of fast T-current was significantly increased only in the neurons of hyperalgesic group. In contrast, the peak current density of slow T-current was significantly decreased in the hypo- and normalgesic groups. Experimental diabetes also resulted in a depolarizing shift of steady-state inactivation of fast T-current in the hyperalgesic group and slow T-current in the hypo- and normalgesic groups. We suggest that the observed changes may contribute to expression of different types of peripheral diabetic neuropathy occurring during the development of diabetes mellitus.
    Neural Plasticity 02/2014; 2014:938235. DOI:10.1155/2014/938235 · 3.58 Impact Factor
Show more