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Differential neurotoxicity of tricyclic antidepressants and novel derivatives in vitro in a dorsal root ganglion cell culture model☆

Published online by Cambridge University Press:  01 August 2007

I. Haller ,
P. Lirk ,
C. Keller ,
G. K. Wang ,
P. Gerner  and
L. Klimaschewski
I. Haller
Affiliation:
Medical University of Innsbruck, Department of Anesthesiology and Critical Care Medicine, Austria Medical University of Innsbruck, Division of Neuroanatomy, Austria
P. Lirk*
Affiliation:
Medical University of Innsbruck, Department of Anesthesiology and Critical Care Medicine, Austria
C. Keller
Affiliation:
Medical University of Innsbruck, Department of Anesthesiology and Critical Care Medicine, Austria
G. K. Wang
Affiliation:
Brigham and Women’s Hospital/Harvard Medical School, Department of Anesthesiology, Perioperative and Pain Medicine, Boston, USA
P. Gerner
Affiliation:
Brigham and Women’s Hospital/Harvard Medical School, Department of Anesthesiology, Perioperative and Pain Medicine, Boston, USA
L. Klimaschewski
Affiliation:
Medical University of Innsbruck, Division of Neuroanatomy, Austria
*
Correspondence to: Philipp Lirk, Department of Anesthesiology and Critical Care Medicine, Medical University of Innsbruck, Anichstr, 35, 6020 Innsbruck, Austria. E-mail: philipp.lirk@i-med.ac.at; Tel: +43 512 504 22400; Fax: +43 512 504 22450
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Summary

Background and objective

Tricyclic antidepressants are commonly employed orally to treat major depressive disorders and have been shown to be of substantial benefit in various chronic pain conditions. Among other properties they are potent Na+ channel blockers in vitro and show local anaesthetic properties in vivo. The present study aimed to determine their differential neurotoxicity, and that of novel derivatives as prerequisite for their potential use in regional anaesthesia.

Methods

To directly test neurotoxicity in adult peripheral neurons, the culture model of dissociated adult rat primary sensory neurons was employed. Neurons were incubated for 24 h with amitriptyline, N-methyl-amitriptyline, doxepin, N-methyl-doxepin, N-propyl-doxepin, desipramine, imipramine and trimipramine at 100 μmol, and at concentrations correlating to their respective potency in blocking sodium channels.

Results

All investigated substances showed considerable neurotoxic potency as represented in significantly decreased neuron numbers in cultures as compared to controls. Specifically, doxepin was more neurotoxic than amitriptyline, and both imipramine and trimipramine were more toxic than desipramine or amitriptyline. Novel derivatives of tricyclic antidepressants were, in general, more toxic than the parent compound.

Conclusions

Tricyclic antidepressants and novel derivatives thereof show differential neurotoxic potential in vitro. The rank order of toxicity relative to sodium channel blocking potency was desipramine < amitriptyline < N-methyl amitriptyline < doxepin < trimipramine < imipramine < N-methyl doxepin < N-propyl doxepin.

Keywords

ANTIDEPRESSIVE AGENTS TRICYCLICANAESTHESIA CONDUCTIONGANGLIA SPINALDRUG TOXICITYNEURONS
Type
Original Article
Information
European Journal of Anaesthesiology , Volume 24 , Issue 8 , August 2007 , pp. 702 - 708
Copyright
Copyright © European Society of Anaesthesiology 2007

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Footnotes

☆

Received from the Department of Anesthesiology and Critical Care Medicine, Medical University of Innsbruck, Austria.

References

1.Pancrazio, J, Kamatchi, G, Roscoe, A et al. . Inhibition of neuronal Na channels by antidepressant drugs. J Pharmacol Exp Ther 1998; 284: 208–214.Google ScholarPubMed
2.Strumper, D, Durieux, ME. Antidepressants as long-acting local anesthetics. Reg Anesth Pain Med 2004; 29: 277–285.CrossRefGoogle ScholarPubMed
3.Gerner, P, Haderer, AE, Mujtaba, M et al. . Assessment of differential blockade by amitriptyline and its N-methyl derivative in different species by different routes. Anesthesiology 2003; 98: 1484–1490.CrossRefGoogle ScholarPubMed
4.LaBuda, CJ, Little, PJ. Pharmacological evaluation of the selective spinal nerve ligation model of neuropathic pain in the rat. J Neurosci Methods 2005; 144: 175–181.CrossRefGoogle ScholarPubMed
5.Fridrich, P, Eappen, S, Jaeger, W et al. . Phase Ia and Ib study of amitriptyline for ulnar nerve block in humans: side effects and efficacy. Anesthesiology 2004; 100: 1511–1518.CrossRefGoogle ScholarPubMed
6.Gerner, P, Kao, G, Srinivasa, V et al. . Topical amitriptyline in healthy volunteers. Reg Anesth Pain Med 2003; 28: 289–293.Google ScholarPubMed
7.Estebe, JP, Myers, RR. Amitriptyline neurotoxicity: dose-related pathology after topical application to rat sciatic nerve. Anesthesiology 2004; 100: 1519–1525.CrossRefGoogle ScholarPubMed
8.Drasner, K, Rigler, ML, Sessler, DI et al. . Cauda equina syndrome following intended epidural anesthesia. Anesthesiology 1992; 77: 582–585.CrossRefGoogle ScholarPubMed
9.Drasner, K, Sakura, S, Chan, VW et al. . Persistent sacral sensory deficit induced by intrathecal local anesthetic infusion in the rat. Anesthesiology 1994; 80: 847–852.CrossRefGoogle ScholarPubMed
10.Drasner, K. Local anesthetic neurotoxicity: clinical injury and strategies that may minimize risk. Reg Anesth Pain Med 2002; 27: 576–580.Google ScholarPubMed
11.Lambert, LA, Lambert, DH, Strichartz, GR. Irreversible conduction block in isolated nerve by high concentrations of local anesthetics. Anesthesiology 1994; 80: 1082–1093.CrossRefGoogle ScholarPubMed
12.Gerner, P. Tricyclic antidepressants and their local anesthetic properties: from bench to bedside and back again. Reg Anesth Pain Med 2004; 29: 286–289.Google Scholar
13.Sudoh, Y, Cahoon, EE, Gerner, P et al. . Tricyclic antidepressants as long-acting local anesthetics. Pain 2003; 103: 49–55.CrossRefGoogle ScholarPubMed
14.Lirk, P, Haller, I, Myers, RR et al. . Mitigation of direct neurotoxic effects of lidocaine and amitriptyline by inhibition of p38 mitogen-activated protein kinase in vitro and in vivo. Anesthesiology 2006; 104: 1266–1273.CrossRefGoogle ScholarPubMed
15.Lirk, P, Haller, I, Hausott, B et al. . The neurotoxic effects of amitriptyline in vitro are dose-dependent, and mediated by apoptosis. Anesth Analg 2006; 102: 1728–1733.CrossRefGoogle ScholarPubMed
16.Popitz-Bergez, FA, Leeson, S, Strichartz, GR et al. . Relation between functional deficit and intraneural local anesthetic during peripheral nerve block. A study in the rat sciatic nerve. Anesthesiology 1995; 83: 583–592.CrossRefGoogle Scholar
17.Gerner, P, Mujtaba, M, Khan, M et al. . N-phenylethyl amitriptyline in rat sciatic nerve blockade. Anesthesiology 2002; 96: 1435–1442.CrossRefGoogle ScholarPubMed
18.Pollock, JE, Neal, JM, Stephenson, CA et al. . Prospective study of the incidence of transient radicular irritation in patients undergoing spinal anesthesia. Anesthesiology 1996; 84: 1361–1367.CrossRefGoogle ScholarPubMed
19.Pollock, JE, Liu, SS, Neal, JM et al. . Dilution of spinal lidocaine does not alter the incidence of transient neurologic symptoms. Anesthesiology 1999; 90: 445–450.CrossRefGoogle Scholar
20.Auroy, Y, Benhamou, D, Bargues, L et al. . Major complications of regional anesthesia in France: The SOS Regional Anesthesia Hotline Service. Anesthesiology 2002; 97: 1274–1280.CrossRefGoogle ScholarPubMed
21.Auroy, Y, Narchi, P, Messiah, A et al. . Serious complications related to regional anesthesia: results of a prospective survey in France. Anesthesiology 1997; 87: 479–486.CrossRefGoogle ScholarPubMed
22.Gold, MS, Reichling, DB, Hampl, KF et al. . Lidocaine toxicity in primary afferent neurons from the rat. J Pharmacol Exp Ther 1998; 285: 413–421.Google ScholarPubMed
23.Johnson, ME, Uhl, CB, Spittler, KH et al. . Mitochondrial injury and caspase activation by the local anesthetic lidocaine. Anesthesiology 2004; 101: 1184–1194.CrossRefGoogle ScholarPubMed