The effect of amitriptyline on ectopic discharge of primary afferent fibers in the L5 dorsal root in a rat model of neuropathic pain.
BACKGROUND
The sodium channel blocker amitriptyline has been shown to inhibit ectopic discharge in injured nerves. In the present study, we characterized ectopic discharges of afferent fibers following L5/L6 spinal nerve ligation (SNL) by their electrophysiological properties and sensitivities to inhibition by amitriptyline in the decentralized L5 dorsal root in SNL rats.


METHODS
Rats exhibiting withdrawal thresholds <4.0 g after SNL were selected for the present study. After laminectomy in pentobarbital-anesthetized rats, the L5 dorsal root was decentralized close to its entry to the spinal cord, and the spontaneous activities of single units were recorded peripherally before and after IV administration of amitriptyline. The mean frequency of afferent fiber activity and instantaneous frequency were measured.


RESULTS
The spontaneous activities of afferent fibers in naïve rats had high frequency (35.23 +/- 6.63 Hz) and pattern discharge based on their instantaneous frequencies and interspike interval distributions. In rats that had received SNL, afferent fibers exhibited spontaneous discharge (mean of 11.05 +/- 3.66 Hz) with an irregular discharge pattern or short bursting activity in some cases. Only 5/13 (38%) afferent fibers from naïve rats showed reduced spontaneous activities after amitriptyline (2 mg/kg, IV), whereas amitriptyline significantly inhibited ectopic discharge in 13/18 (72%) afferent fibers from SNL rats (ID(50) = 1.66 +/- 0.17 mg/kg). Furthermore, the greatest inhibitory effect of amitriptyline was consistently observed on those afferent fibers exhibiting low frequency (<20 Hz) and/or bursting discharge.


CONCLUSIONS
These results provide direct evidence that amitriptyline, which is used clinically for the treatment of neuropathic pain, selectively inhibits ectopic discharge of low frequency and bursting discharge in the rat neuropathic pain model.
Su
Xin
X
Department of Pain Research, Merck Research Laboratories, West Point, Pennsylvania, USA. xin.su@medtronic.co
Liang
Annie H
AH
Urban
Mark O
MO
D000200:Action Potentials; D000639:Amitriptyline / Q000008:administration & dosage / Q000494:pharmacology*; D000700:Analgesics / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D007275:Injections, Intravenous; D007796:Laminectomy; D008026:Ligation; D008159:Lumbar Vertebrae; D008297:Male; D009437:Neuralgia / Q000188:drug therapy* / Q000503:physiopathology; D009475:Neurons, Afferent / Q000187:drug effects* / Q000378:metabolism; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D026941:Sodium Channel Blockers / Q000008:administration & dosage / Q000494:pharmacology*; D013126:Spinal Nerve Roots / Q000187:drug effects* / Q000503:physiopathology / Q000601:surgery; D013997:Time Factors
D000700:Analgesics; D026941:Sodium Channel Blockers; D000639:Amitriptyline