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Open Access Highly Accessed Research article

Pretreatment with intrathecal amitriptyline potentiates anti-hyperalgesic effects of post-injury intra-peritoneal amitriptyline following spinal nerve ligation

Kuang-I Cheng123, Hung-Chen Wang14, Lin-Li Chang5, Fu-Yen Wang12, Chung-Sheng Lai67*, Chao-Wen Chou1, Hung-Pei Tsai1 and Aij-Lie Kwan68*

Author Affiliations

1 Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, R.O.C

2 Department of Anesthesiology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan, R.O.C

3 Department of Anesthesiology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, R.O.C

4 Department of Neurosurgery, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung, University College of Medicine, Kaohsiung, Taiwan, R.O.C

5 Department of Microbiology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, R.O.C

6 Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, R.O.C

7 Division of Plastic and Reconstructive Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan, R.O.C

8 Department of Neurosurgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan, R.O.C

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BMC Neurology 2012, 12:44  doi:10.1186/1471-2377-12-44

Published: 21 June 2012

Abstract

Background

Amitriptyline, a tricyclic antidepressant and potent use-dependent blocker of sodium channels, has been shown to attenuate acute and chronic pain in several preclinical modes. The purpose of this study was to investigate whether intrathecal pretreatment with amitriptyline combined with post-injury intra-peritoneal amitriptyline is more effective than post-injury treatment alone on L5 spinal nerve ligation (SNL)-induced neuropathic pain.

Methods

96 adult male Sprague–Dawley rats were allocated into 4 groups: group S,

    S
ham; group L, L5 spinal nerve
    L
igation with vehicle treatment; group A, SNL and post-injury intra-peritoneal (
    A
bdominal) amitriptyline twice daily × 3 days; group P, intrathecal
    P
retreatment with amitriptyline, SNL and intra-peritoneal amitriptyline twice daily × 3 days. Responses to thermal and mechanical stimuli, as well as sodium channel expression in injured dorsal root ganglion (DRG) and activated glial cells in spinal dorsal horn (SDH) were measured pre-operatively and on post-operative day (POD) 4, 7, 14, 21 and 28.

Results

SNL-evoked hyper-sensitivity responses to thermal and mechanical stimuli, up-regulated Nav1.3 and down-regulated Nav1.8 expression in DRG, and activated microglia and astrocytes in SDH. In group A, intra-peritoneal amitriptyline alone alleviated thermal hypersensitivity on POD7, reversed Nav1.8 and reduced activated microglia on POD14. In group P, intrathecal pretreatment with amitriptyline not only potentiated the effect of intra-peritoneal amitriptyline on thermal hypersensitivity and Nav1.8, but attenuated mechanical hypersensitivity on POD7 and reduced up-regulated Nav1.3 on POD14. Furthermore, this treatment regimen reduced astrocyte activation on POD14.

Conclusions

Concomitant intrathecal pretreatment and post-injury intra-peritoneal amitriptyline was more effective than post-injury treatment alone on attenuation of behavioral hypersensitivity, decrease of activated microglia and astrocytes and dysregulated Nav1.3 and 1.8.

Keywords:
Intrathecal amitriptyline; Allodynia; Sodium channels; Microglia; Astrocyte