Share this article on:

Amitriptyline, but Not Pregabalin, Reverses the Attenuation of Noxious Stimulus–Induced Analgesia After Nerve Injury in Rats

Matsuoka, Hiroaki MD; Suto, Takashi MD, PhD; Saito, Shigeru MD, PhD; Obata, Hideaki MD, PhD

doi: 10.1213/ANE.0000000000001301
Pain and Analgesic Mechanisms: Original Laboratory Research Report

BACKGROUND: Noxious stimulus–induced analgesia (NSIA) is a type of conditioned pain modulation in rats that has been used to assess endogenous pain control systems. The descending noradrenergic system is involved in NSIA, and nerve injury induces plastic changes of descending noradrenergic neurons. Thus, we hypothesized that nerve injury would affect NSIA strength and that amitriptyline and pregabalin, which often are used for treating neuropathic pain, might further modulate NSIA through effects on the descending noradrenergic system.

METHODS: We examined the change in NSIA over time after right L5 spinal nerve ligation (SNL) in rats by measuring the contralateral hind paw withdrawal threshold after left forepaw capsaicin injection. In addition, we examined NSIA after 5 daily intraperitoneal injection of amitriptyline or pregabalin. Microdialysis studies were performed to measure noradrenaline levels after left forepaw capsaicin injection in the left spinal dorsal horn in noninjured rats, SNL rats, and SNL rats that had received 5 daily intraperitoneal injections of amitriptyline or pregabalin.

RESULTS: NSIA was dramatically attenuated 5 and 6 weeks after SNL (P < 0.001). The noradrenaline level in the lumbar spinal cord was significantly increased in noninjured rats receiving forepaw injection of capsaicin compared with vehicle injection (P < 0.001), but not in rats 6 weeks after SNL surgery. Five daily intraperitoneal injections of amitriptyline (10 mg/kg/d) or pregabalin (10 mg/kg/d) at 5 weeks after SNL gradually increased the ipsilateral hindpaw withdrawal threshold (P < 0.001). At 6 weeks after SNL, amitriptyline, but not pregabalin, reversed the attenuation of NSIA by SNL (P < 0.001) and increased the spinal noradrenaline level after forepaw injection of capsaicin (P = 0.005).

CONCLUSIONS: These data suggest that endogenous analgesia in neuropathic pain states is strongly decreased from a certain time after nerve injury and that amitriptyline reverses the attenuation of endogenous analgesia through effects on the descending noradrenergic system.

Published ahead of print April 15, 2016

From the Department of Anesthesiology, Gunma University Graduate School of Medicine, Gunma, Japan.

Accepted for publication January 28, 2016.

Published ahead of print April 15, 2016

Funding: The study was supported by Grants-in-Aid for Scientific Research (KAKENHI) from the Ministry of Education, Culture, Sports, Scientific and Technology of Japan (grant no. 25861356 to Dr. Matsuoka and grant no. 26670678 to Dr. Obata).

The authors declare no conflicts of interest.

Reprints will not be available from the authors.

Address correspondence to Hideaki Obata, MD, PhD, Department of Anesthesiology, Gunma University Graduate School of Medicine, 3-39-22, Showa-machi, Maebashi, Gunma 371–8511, Japan. Address e-mail to

© 2016 International Anesthesia Research Society