Paclitaxel-induced increase in NCX activity in subpopulations of nociceptive afferents: A protective mechanism against chemotherapy-induced peripheral neuropathy?
There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.
Abstract
<p class="first" id="P1">We recently demonstrated, in a rat model of chemotherapy-induced
peripheral neuropathy
(CIPN), that there is a significant decrease in the duration of the depolarization-evoked
Ca
<sup>2+</sup> transient in isolated somata of putative nociceptive afferents innervating
the glabrous
skin of the hindpaw, but no change in transient magnitude or the resting concentration
of intracellular Ca
<sup>2+</sup> ([Ca
<sup>2+</sup>]
<sub>i</sub>). Because the Na
<sup>+</sup>-Ca
<sup>2+</sup> exchanger (NCX) only contributes to the regulation of the duration of
the evoked
Ca
<sup>2+</sup> transient, in putative nociceptive dorsal root ganglion (DRG) neurons,
we hypothesized
that an increase in NCX activity underlies the CIPN-induced change in this subpopulation
of neurons. Acutely dissociated retrogradely labeled sensory neurons from naïve, vehicle-,
and paclitaxel-treated rats were studied with fura-2 based Ca
<sup>2+</sup> imaging. There was no difference in the relative level of NCX activity
between glabrous
neurons from paclitaxel-treated or control rats. However, in contrast to the relatively
large and long lasting Ca
<sup>2+</sup> transients needed to evoke NCX activity in neurons from naïve rats,
there was evidence
of resting NCX activity in glabrous neurons from both vehicle- and paclitaxel-treated
rats. More interestingly, there was a paclitaxel-induced increase in NCX activity
in putative nociceptive neurons innervating the thigh, neurons in which there is no
evidence of a change in the depolarization-induced Ca
<sup>2+</sup> transient, or a body site in which there was a change in nociceptive
threshold. Furthermore,
while the majority of NCX activity in glabrous neurons is sensitive to the NCX3-preferring
blocker KB-R7943, the increase in NCX activity in thigh neurons was resistant to KB-R7943
but sensitive to the NCX1-preferring blocker SEA0400. These results suggest that a
mechanism(s) other than NCX underlies the paclitaxel-induced decrease in the duration
of the evoked Ca
<sup>2+</sup> transient in putative nociceptive glabrous skin neurons. However, the
compensatory
response to paclitaxel observed may also explain why only subpopulations of sensory
neurons are impacted by paclitaxel, raising the intriguing possibility that CIPN is
due to the failure of injured neurons to appropriately compensate for the deleterious
consequences of this compound.
</p><p id="P2">
<div class="figure-container so-text-align-c">
<img alt="" class="figure" src="/document_file/9623a48d-785e-47c8-86ae-80254442f143/PubMedCentral/image/nihms785159f5.jpg"/>
</div>
</p>