Intravenous paclitaxel administration in the rat induces a peripheral sensory neuropathy characterized by macrophage infiltration and injury to sensory neurons and their supporting cells

Peters, Christopher M.; Jiménez-Andrade, Juan Miguel; Jonas, Beth M.; Sevcik, Molly A.; Koewler, Nathan J.; Ghilardi, Joseph R.; Wong, Gilbert Y.; Mantyh, Patrick W.

doi:10.1016/j.expneurol.2006.07.022

Cited by 256 publications

(213 citation statements)

References 69 publications

Supporting

Mentioning

190

Contrasting

Unclassified

Order By: Relevance

“…The neuronal cell soma area was determined in DRG of paclitaxel-treated rats for a minimum of 700 neuronal profiles per time point. Previously, we observed that large > medium > small diameter sensory neurons expressed ATF3 ten days following paclitaxel administration (Peters et al, 2007). This pattern was also observed in the current study at earlier time points including days 4 and 6 post initial infusion.…”

Section: Cell Size Distribution Of Neuronal Atf3 Expression In Drg Ofsupporting

confidence: 90%

“…This cellular pathology was accompanied by behavioral changes indicative of a sensory neuropathy including cold and mechanical allodynia as well as behavioral deficits in coordination (Peters et al, 2007). Examination of sensory ganglia at multiple levels of the neuroaxis revealed that the cellular pathology occurred in a length dependent manner (Jimenez-Andrade et al, 2006) similar to the pattern of symptoms observed in patients treated with taxanes.…”

Section: Introductionmentioning

confidence: 74%

“…Results are reported as the percentage of labeled cells within each size population according to previously established size criteria (Obata et al, 2003) small (<600 μm 2 ), medium (600-1200 μm 2 ) and large (>1200 μm 2 ) neurons. The number of nodules of Nageotte was determined by counting the total number of clusters (> 8 adjacent nuclei) of ATF3-IR satellite cells in the entire area of a DRG section from a total of 4 sections per ganglion (Peters et al, 2007).…”

Section: Quantification/ Image Analysismentioning

confidence: 99%

“…To assess satellite cell activation in the DRG, GFAP immunofluorescence (IF) levels were quantified (Peters et al, 2007). Satellite cells have been shown to increase the levels of GFAP expression as well as increase their size following peripheral nerve injury (Woodham et al, 1989;Shinder & Devor, 1994).…”

Section: Quantification/ Image Analysismentioning

confidence: 99%

“…Recently, using a previously characterized model of PIPN (Cliffer et al, 1998), we demonstrated pathological features in the dorsal root ganglia (DRG) and sciatic nerve ten days following intravenous administration of paclitaxel in rats (Peters et al, 2007). This cellular pathology was accompanied by behavioral changes indicative of a sensory neuropathy including cold and mechanical allodynia as well as behavioral deficits in coordination (Peters et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

An evolving cellular pathology occurs in dorsal root ganglia, peripheral nerve and spinal cord following intravenous administration of paclitaxel in the rat

et al. 2007

Self Cite

View full text Add to dashboard Cite

Paclitaxel (Taxol®) is a frontline antineoplastic agent used to treat a variety of solid tumors including breast, ovarian, or lung cancer. The major dose limiting side effect of paclitaxel is a 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/regeneration (activating transcription factor 3; ATF3), macrophage hyperplasia/hypertrophy; satellite cell hypertrophy in the dorsal root ganglion (DRG) and sciatic nerve as well as astrocyte and microglial activation within the spinal cord at 1, 4, 6 and 10 days following intravenous infusion of therapeutically relevant doses of paclitaxel. At day 1 post-infusion there was an up-regulation of ATF3 in a subpopulation of large and small DRG neurons and 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 in the spinal cord were not observed until day 6 post 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 therapies to attenuate or block this frequently painful and debilitating condition.

show abstract

Section: Cell Size Distribution Of Neuronal Atf3 Expression In Drg Ofsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 74%

Section: Quantification/ Image Analysismentioning

confidence: 99%

Section: Quantification/ Image Analysismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

An evolving cellular pathology occurs in dorsal root ganglia, peripheral nerve and spinal cord following intravenous administration of paclitaxel in the rat

et al. 2007

Self Cite

View full text Add to dashboard Cite

show abstract

Further data supporting that paclitaxel‐associated acute pain syndrome is associated with development of peripheral neuropathy

Reeves

Dakhil²,

Sloan

et al. 2012

Cancer

142

109

View full text Add to dashboard Cite

Background Paclitaxel causes an acute pain syndrome (P-APS), occurring within days after each dose and usually abating within days. Paclitaxel also causes a more classic peripheral neuropathy, which steadily increases in severity with increasing paclitaxel total doses. Little detail is available regarding the natural history of these two syndromes, or any relationship between them, although a recent publication does provide natural history data about weekly paclitaxel, supporting an association between the severity of P-APS and eventual peripheral neuropathy symptoms. Methods Patients entering this study were about to receive paclitaxel and carboplatin every 3 weeks. Daily questionnaires were completed for the first week after every chemotherapy dose and EORTC QLQ-CIPN 20 instruments were completed weekly. Results The P-APS severity peaked on day 4 after the initial chemotherapy dose, with 12%, 29%, 23%, and 36% of patients having maximal pain scores of 0, 1–4, 5–6, or 7–10 during the first week after the first dose of therapy, respectively. Patients with P-APS scores of 0–4 with the first dose of chemotherapy had less eventual sensory neuropathy than did patients with P-APS scores of 5–10 (p=0.001). With regard to the more peripheral neuropathy, sensory neuropathy was more problematic than was either motor or autonomic neuropathy. Numbness and tingling were more common components of the sensory neuropathy, than was pain. Conclusions Patients with worse P-APS severities appear to have more eventual chemotherapy induced peripheral neuropathy. This provides support for the concept that the P-APS is a form of nerve pathology.

show abstract

Microglia and neuropathic pain

Inoue

Tsuda

2009

Glia

253

192

View full text Add to dashboard Cite

In contrast to physiological pain, pathological pain is not dependent on the presence of tissue-damaging stimuli. One type of pathological pain--neuropathic pain--is often a consequence of nerve injury or of diseases such as diabetes, AIDS, or cancer. Neuropathic pain can be agonizing, can persist over long periods, and, unfortunately, is often resistant to known painkillers. There is a rapidly growing body of evidence indicating that microglia, the CNS immune cells, have causal roles in the pathogenesis of pain hypersensitivity following nerve injury. We will review recent advances in our understanding of the mechanisms producing neuropathic pain, focusing on the roles of microglia-expressed molecules, including cell surface receptors, intracellular signaling molecules, and diffusible factors involved in nerve injury-induced pain behaviors and hyperexcitability of dorsal horn neurons. Elucidating how spinal microglia cause neuropathic pain may provide us with exciting insights into pain mechanisms and clues for developing new drugs for the treatment of neuropathic pain.

show abstract

Intravenous paclitaxel administration in the rat induces a peripheral sensory neuropathy characterized by macrophage infiltration and injury to sensory neurons and their supporting cells

Cited by 256 publications

References 69 publications

An evolving cellular pathology occurs in dorsal root ganglia, peripheral nerve and spinal cord following intravenous administration of paclitaxel in the rat

An evolving cellular pathology occurs in dorsal root ganglia, peripheral nerve and spinal cord following intravenous administration of paclitaxel in the rat

Further data supporting that paclitaxel‐associated acute pain syndrome is associated with development of peripheral neuropathy

Microglia and neuropathic pain

Contact Info

Product

Resources

About