Paclitaxel Causes Electrophysiological Changes in the Anterior Cingulate Cortex Via Modulation of the γ-Aminobutyric Acid-ergic System

Overview

Journal Med Princ Pract

Publisher Karger

Specialties General Medicine
Medical Education

Date 2016 Jun 24

PMID 27336416

Citations 13

Authors

Houda Nashawi

Willias Masocha

Ivan O Edafiogho

Samuel B Kombian

Affiliations

Soon will be listed here.

Abstract

Objective: The aim of this study was to elucidate any electrophysiological changes that may contribute to the development of neuropathic pain during treatment with the anticancer drug paclitaxel, particularly in the γ-aminobutyric acid (GABA) system.

Materials And Methods: One hundred and eight Sprague-Dawley rats were used (untreated control: 43; vehicle-treated: 21, and paclitaxel-treated: 44). Paclitaxel (8 mg/kg) was administered intraperitoneally on 2 alternate days to induce mechanical allodynia. The rats were sacrificed 7 days after treatment to obtain slices of the anterior cingulate cortex (ACC), a brain region involved in the central processing of pain. Field excitatory postsynaptic potentials (fEPSPs) were recorded in layer II/III of ACC slices, and stimulus-response curves were constructed. The observed effects were pharmacologically characterized by bath application of GABA and appropriate drugs to the slices.

Results: The paclitaxel-treated rats developed mechanical allodynia (i.e. reduced withdrawal threshold to mechanical stimuli). Slices from paclitaxel-treated rats produced a significantly higher maximal response (Emax) than those from untreated rats (p < 0.001). Bath application of GABA (0.4 µM) reversed this effect and returned the excitability to a level similar to control. Pretreatment of the slices with the GABAB receptor blocker CGP 55845 (50 µM) increased Emax in slices from untreated rats (p < 0.01) but not from paclitaxel-treated rats.

Conclusion: In this study, there was a GABA deficit in paclitaxel-treated rats compared to untreated ones. Such a deficit could contribute to the pathophysiology of paclitaxel-induced neuropathic pain (PINP). Thus, the GABAergic system might be a potential therapeutic target for managing PINP.

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References

Edafiogho I, Hinko C, Chang H, Moore J, Mulzac D, Nicholson J . Synthesis and anticonvulsant activity of enaminones. J Med Chem. 1992; 35(15):2798-805. DOI: 10.1021/jm00093a012. View

Kemper E, van Zandbergen A, Cleypool C, Mos H, Boogerd W, Beijnen J . Increased penetration of paclitaxel into the brain by inhibition of P-Glycoprotein. Clin Cancer Res. 2003; 9(7):2849-55. View

Zeilhofer H, Mohler H, Di Lio A . GABAergic analgesia: new insights from mutant mice and subtype-selective agonists. Trends Pharmacol Sci. 2009; 30(8):397-402. DOI: 10.1016/j.tips.2009.05.007. View

Yamashita A, Hamada A, Suhara Y, Kawabe R, Yanase M, Kuzumaki N . Astrocytic activation in the anterior cingulate cortex is critical for sleep disorder under neuropathic pain. Synapse. 2014; 68(6):235-47. DOI: 10.1002/syn.21733. View

Yadav R, Yan X, Maixner D, Gao M, Weng H . Blocking the GABA transporter GAT-1 ameliorates spinal GABAergic disinhibition and neuropathic pain induced by paclitaxel. J Neurochem. 2015; 133(6):857-69. PMC: 4464967. DOI: 10.1111/jnc.13103. View

Nishida K, Kuchiiwa S, Oiso S, Futagawa T, Masuda S, Takeda Y . Up-regulation of matrix metalloproteinase-3 in the dorsal root ganglion of rats with paclitaxel-induced neuropathy. Cancer Sci. 2008; 99(8):1618-25. PMC: 11159700. DOI: 10.1111/j.1349-7006.2008.00877.x. View

Kombian S, Edafiogho I, Ananthalakshmi K . Anticonvulsant enaminones depress excitatory synaptic transmission in the rat brain by enhancing extracellular GABA levels. Br J Pharmacol. 2005; 145(7):945-53. PMC: 1576207. DOI: 10.1038/sj.bjp.0706250. View

Xu H, Wu L, Wang H, Zhang X, Vadakkan K, Kim S . Presynaptic and postsynaptic amplifications of neuropathic pain in the anterior cingulate cortex. J Neurosci. 2008; 28(29):7445-53. PMC: 3844787. DOI: 10.1523/JNEUROSCI.1812-08.2008. View

Glantz M, Choy H, Kearns C, Mills P, Wahlberg L, Zuhowski E . Paclitaxel disposition in plasma and central nervous systems of humans and rats with brain tumors. J Natl Cancer Inst. 1995; 87(14):1077-81. DOI: 10.1093/jnci/87.14.1077. View

10.

Scripture C, Figg W, Sparreboom A . Peripheral neuropathy induced by paclitaxel: recent insights and future perspectives. Curr Neuropharmacol. 2008; 4(2):165-72. PMC: 2430667. DOI: 10.2174/157015906776359568. View

11.

Hershman D, Lacchetti C, Dworkin R, Smith E, Bleeker J, Cavaletti G . Prevention and management of chemotherapy-induced peripheral neuropathy in survivors of adult cancers: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2014; 32(18):1941-67. DOI: 10.1200/JCO.2013.54.0914. View

12.

Erikson K, Shihabi Z, Aschner J, Aschner M . Manganese accumulates in iron-deficient rat brain regions in a heterogeneous fashion and is associated with neurochemical alterations. Biol Trace Elem Res. 2002; 87(1-3):143-56. DOI: 10.1385/BTER:87:1-3:143. View

13.

Wu C, Sun D . GABA receptors in brain development, function, and injury. Metab Brain Dis. 2014; 30(2):367-79. PMC: 4231020. DOI: 10.1007/s11011-014-9560-1. View

14.

Masocha W . Comprehensive analysis of the GABAergic system gene expression profile in the anterior cingulate cortex of mice with Paclitaxel-induced neuropathic pain. Gene Expr. 2015; 16(3):145-53. PMC: 8750099. DOI: 10.3727/105221615X14181438356337. View

15.

Tseng M, Chiang M, Chao C, Tseng W, Hsieh S . fMRI evidence of degeneration-induced neuropathic pain in diabetes: enhanced limbic and striatal activations. Hum Brain Mapp. 2012; 34(10):2733-46. PMC: 6869882. DOI: 10.1002/hbm.22105. View

16.

Xie Y, Huo F, Tang J . Cerebral cortex modulation of pain. Acta Pharmacol Sin. 2008; 30(1):31-41. PMC: 4006538. DOI: 10.1038/aps.2008.14. View

17.

Thangamani D, Edafiogho I, Masocha W . The anticonvulsant enaminone E139 attenuates paclitaxel-induced neuropathic pain in rodents. ScientificWorldJournal. 2014; 2013:240508. PMC: 3872104. DOI: 10.1155/2013/240508. View

18.

Edafiogho I, Kombian S, Ananthalakshmi K, Salama N, Eddington N, Wilson T . Enaminones: Exploring additional therapeutic activities. J Pharm Sci. 2007; 96(10):2509-31. DOI: 10.1002/jps.20967. View