Stimulation of Cutaneous Low Threshold Mechanoreceptors in Mice After Intracolonic Capsaicin Increases Spinal c-Fos Labeling in an NKCC1-Dependent Fashion

Stimulation of peripheral nociceptors results in increased c-Fos labeling in spinal cord regions associated with nociceptive processing. Accordingly, intracolonic capsaicin, which generates robust secondary (referred) allodynia on the abdomen of mice, also causes an increased spinal c-Fos labeling. In naïve rodents, low intensity innocuous stimulation does not affect c-Fos labeling in spinal nociceptive regions. However, after persistent noxious input, low intensity stimulation of the inflamed region further enhances c-Fos labeling, suggesting that low threshold mechanosensitive fibers gain access to the nociceptive channel after persistent inflammation. We have previously proposed that afferent activity in low threshold sensory fibers activates nociceptive sensory fibers through Na+-K+-Cl− cotransporter 1 (NKCC1) -mediated enhanced primary afferent depolarization. Here, we show that intracolonic capsaicin enhances spinal c-Fos labeling and secondary allodynia in an NKCC1-dependent manner. Furthermore, we demonstrate that gently brushing the abdomen, the region of secondary allodynia, further increased spinal c-Fos levels, an effect that can be prevented by spinal NKCC1 blockade. These findings provide evidence that increased NKCC1 activity contributes to secondary allodynia and that innocuous touch can access the nociceptive channel in part through enhanced NKCC1 activity.PerspectiveWhile touch normally soothes acute pain, we demonstrate that following peripheral inflammation, touch evokes pain (allodynia) through the switching of a normally inhibitory spinal pathway into an excitatory pathway. Activation of low threshold mechanoreceptors activates spinal nociceptive neurons following inflammation-induced enhancement of NKCC1 expression, as measured by spinal c-Fos labeling.