Low concentrations of amitriptyline inhibit nicotinic receptors in unmyelinated axons of human peripheral nerve
Article first published online: 19 AUG 2009
© 2009 The Authors. Journal compilation © 2009 The British Pharmacological Society
British Journal of Pharmacology
Volume 158, Issue 3, pages 797–805, October 2009
How to Cite
Freysoldt, A., Fleckenstein, J., Lang, P., Irnich, D., Grafe, P. and Carr, R. (2009), Low concentrations of amitriptyline inhibit nicotinic receptors in unmyelinated axons of human peripheral nerve. British Journal of Pharmacology, 158: 797–805. doi: 10.1111/j.1476-5381.2009.00347.x
- Issue published online: 14 OCT 2009
- Article first published online: 19 AUG 2009
- Received 9 March 2009; accepted 17 April 2009
- neuropathic pain;
- axonal excitability;
- nociceptive nerve fibres;
- neuronal nicotinic receptors
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 (EC50 2.6 µM) 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.