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Low concentrations of amitriptyline inhibit nicotinic receptors in unmyelinated axons of human peripheral nerve.

Abstract：

BACKGROUND AND PURPOSE:Amitriptyline is often prescribed as a first-line treatment for neuropathic pain but its precise mode of analgesic action remains uncertain. Amitriptyline is known to inhibit voltage-dependent ion channels and also to act as an antagonist at ligand-gated ion channels, such as nicotinic acetylcholine receptors (nAChRs). In the present study, we tested the effect of amitriptyline on nicotinic responses of unmyelinated axons in isolated segments of human peripheral nerve. In particular, a comparison was made between the concentrations of amitriptyline necessary for inhibition of nAChRs and those required for inhibition of the compound C-fibre action potential. EXPERIMENTAL APPROACH:Isolated axon fascicles were prepared from short segments of human sural nerve, and multiple measures of axonal excitability were recorded using computer-controlled threshold tracking software. KEY RESULTS:Amitriptyline (EC(50) 2.6 microM) reduced the nicotine-induced increase in C-fibre excitability but only slightly altered the amplitude and latency to onset of the compound action potential. In contrast, tetrodotoxin produced a clear reduction in the amplitude and a prolongation of action potential onset latency but was without effect on the nicotine-induced increase in axonal excitability. CONCLUSIONS AND IMPLICATIONS:These data demonstrate that low concentrations of amitriptyline suppress the response of human peripheral C-type axons to nicotine by directly inhibiting nAChRs. Blockade of tetrodotoxin-sensitive, voltage-dependent sodium channels does not contribute to this effect. An inhibitory action of amitriptyline on nAChRs in unmyelinated nociceptive axons may be an important component of amitriptyline's therapeutic effect in the treatment of neuropathic pain.

journal_name

Br J Pharmacol

journal_title

British journal of pharmacology

authors

Freysoldt A,Fleckenstein J,Lang PM,Irnich D,Grafe P,Carr RW

doi

10.1111/j.1476-5381.2009.00347.x

subject

Has Abstract

pub_date

2009-10-01 00:00:00

pages

797-805

issue

eissn

0007-1188

issn

1476-5381

pii

BPH347

journal_volume

158

pub_type

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Low concentrations of amitriptyline inhibit nicotinic receptors in unmyelinated axons of human peripheral nerve.