Brain Research

BRAIN RESEARCH 1168 (2007) 46–59

a v a i l a b l e a t w w w. s c i e n c e d i r e c t . c o m

w w w. e l s e v i e r. c o m / l o c a t e / b r a i n r e s

Research Report

An evolving cellular pathology occurs in dorsal root ganglia,
peripheral nerve and spinal cord following intravenous
administration of paclitaxel in the rat
Christopher M. Peters a , Juan Miguel Jimenez-Andradea , Michael A. Kuskowski f ,
Joseph R. Ghilardi e , Patrick W. Mantyh a,b,c,d,e,⁎
a

Department of Diagnostic & Biological Sciences, University of Minnesota, Minneapolis, MN 55455, USA
Department of Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA
c
Department of Psychiatry, University of Minnesota, Minneapolis, MN 55455, USA
d
Cancer Center, University of Minnesota,Minneapolis, MN 55455, USA
e
Research Service, VA Medical Center, Minneapolis, MN 55417, USA
f
GRECC, VA Medical Center, Minneapolis, MN 55417, USA
b

ARTICLE INFO

ABSTRACT

Article history:

Paclitaxel (Taxol®) is a frontline antineoplastic agent used to treat a variety of solid tumors

Accepted 8 June 2007

including breast, ovarian, or lung cancer. The major dose limiting sideeffect of paclitaxel is a

Available online 17 July 2007

peripheral sensory neuropathy that can last days to a lifetime. To begin to understand the
cellular events that contribute to this neuropathy, we examined a marker of cell injury/

Keywords:

regeneration (activating transcription factor 3; ATF3), macrophage hyperplasia/hypertrophy;

Neuropathic pain

satellite cell hypertrophyin the dorsal root ganglia (DRG) and sciatic nerve as well as

Taxane

astrocyte and microglial activation within the spinal cord at 1, 4, 6 and 10 days following

Neurotoxicity

intravenous infusion of therapeutically relevant doses of paclitaxel. At day 1 post-infusion,

Breast cancer

there was an up-regulation of ATF3 in a subpopulation of large and small DRG neurons andVincristine

this up-regulation was present through day 10. In contrast, hypertrophy of DRG satellite
cells, hypertrophy and hyperplasia of CD68+ macrophages in the DRG and sciatic nerve, ATF3
expression in S100β+ Schwann cells and increased expression of the microglial marker
(CD11b) and the astrocyte marker glial fibrillary acidic protein (GFAP) in the spinal cord were
not observed until day 6post-infusion. The present results demonstrate that using the time
points and markers examined, DRG neurons show the first sign of injury which is followed
days later by other neuropathological changes in the DRG, peripheral nerve and dorsal horn
of the spinal cord. Understanding the cellular changes that generate and maintain this
neuropathy may allow the development of mechanism-based therapiesto attenuate or block
this frequently painful and debilitating condition.
© 2007 Elsevier B.V. All rights reserved.

⁎ Corresponding author. Neurosystems Center, 18-208 Moos Tower, University of Minnesota, 515 Delaware Street SE, Minneapolis, MN
55455, USA. Fax: +1 612 626 2565.
E-mail address: manty001@umn.edu (P.W. Mantyh).
0006-8993/$ – see front matter © 2007 Elsevier B.V. All rightsreserved.
doi:10.1016/j.brainres.2007.06.066

BRAIN RESEARCH 1168 (2007) 46–59

1.

Introduction

Administration of the chemotherapeutic agent paclitaxel can
induce a dose-dependent peripheral sensory neuropathy in a
subset of patients receiving this therapy for breast, ovarian, and
non-small cell lung cancer (Lee and Swain, 2006; Mielke et al.,
2006). Following administration ofpaclitaxel patients may
experience a range of positive sensory symptoms including
spontaneous tingling, burning pain, joint and muscle pain
(Postma et al., 1995; Quasthoff and Hartung, 2002; Dougherty
et al., 2004) that often occur in the distal extremities in a “glove

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and stocking” distribution. These symptoms may increase in
severity and be accompanied by sensory deficits including...