Astrocyte activation in the anterior cingulate cortex and altered glutamatergic gene expression during paclitaxel-induced neuropathic pain in mice.

Willias Masocha

doi:10.7717/peerj.1350

Abstract

Spinal astrocyte activation contributes to the pathogenesis of paclitaxel-induced neuropathic pain (PINP) in animal models. We examined glial fibrillary acidic protein (GFAP; an astrocyte marker) immunoreactivity and gene expression of GFAP, glutamate transporters and receptor subunits by real time PCR in the anterior cingulate cortex (ACC) at 7 days post first administration of paclitaxel, a time point when mice had developed thermal hyperalgesia. The ACC, an area in the brain involved in pain perception and modulation, was chosen because changes in this area might contribute to the pathophysiology of PINP. GFAP transcripts levels were elevated by more than fivefold and GFAP immunoreactivity increased in the ACC of paclitaxel-treated mice. The 6 glutamate transporters (GLAST, GLT-1 EAAC1, EAAT4, VGLUT-1 and VGLUT-2) quantified were not significantly altered by paclitaxel treatment. Of the 12 ionotropic glutamate receptor subunits transcripts analysed 6 (GLuA1, GLuA3, GLuK2, GLuK3, GLuK5 and GLuN1) were significantly up-regulated, whereas GLuA2, GLuK1, GLuK4, GLuN2A and GLuN2B were not significantly altered and GLuA4 was lowly expressed. Amongst the 8 metabotropic receptor subunits analysed only mGLuR8 was significantly elevated. In conclusion, during PINP there is astrocyte activation, with no change in glutamate transporter expression and differential up-regulation of glutamate receptor subunits in the ACC. Thus, targeting astrocyte activation and the glutamatergic system might be another therapeutic avenue for management of PINP.

Highlights

The anterior cingulate cortex (ACC) is a cortical area in the brain that has been described to be involved with pain, possibly including both perception and modulation (Vogt, 2005; Xie, Huo & Tang, 2009; Zhuo, 2008)
Paclitaxel-induced thermal hyperalgesia Mice developed thermal hyperalgesia on day 7 after first administration of paclitaxel as we previously described (Masocha, 2014; Parvathy & Masocha, 2013) i.e., paclitaxel-treated mice had significant reduction in response latency time in the hot plate test on day 7 compared to the baseline latency and vehicle-treated animals (6.23 ± 0.28 s compared to 9.66 ± 0.16 s and 9.00 ± 0.38 s, respectively; n = 10 vehicle-treated mice and 16 paclitaxel treated-mice; p < 0.05 for both comparisons)
Treatment with paclitaxel significantly increased the expression of glial fibrillary acidic protein (GFAP) transcripts (p = 0.02) by more than fivefold compared to vehicle-treated controls (Fig. 1)

Summary

Introduction

The anterior cingulate cortex (ACC) is a cortical area in the brain that has been described to be involved with pain, possibly including both perception and modulation (Vogt, 2005; Xie, Huo & Tang, 2009; Zhuo, 2008). It is a component of the medial pain pathway. Neuroimaging studies have shown increased activity in the ACC during chronic pain, including neuropathic pain (Hsieh et al, 1995; Peyron, Laurent & Garcia-Larrea, 2000; Tseng et al, 2013). Neurophysiological and molecular changes have been observed in the ACC during chronic or neuropathic (Wrigley et al, 2009; Xu et al, 2008; Yamashita et al, 2014)

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