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Intrathecal ultra-low dose naloxone enhances the antihyperalgesic effects of morphine and attenuates tumor necrosis factor-alpha and tumor necrosis factor-alpha receptor 1 expression in the dorsal horn of rats with partial sciatic nerve transection.

Authors: Yang, CP  Cherng, CH  Wu, CT  Huang, HY  Tao, PL  Lee, SO  Wong, CS 
Citation: Yang CP, etal., Anesth Analg. 2013 Dec;117(6):1493-502. doi: 10.1213/ANE.0000000000000020.
Pubmed: (View Article at PubMed) PMID:24257399
DOI: Full-text: DOI:10.1213/ANE.0000000000000020

BACKGROUND: Glutamate homeostasis and microglia activation play an important role in the development and maintenance of neuropathic pain. We designed this investigation to examine whether ultra-low dose naloxone administered alone or in combination with morphine could alter the concentration of the excitatory amino acids (EAAs) glutamate and aspartate, as well as the expression of tumor necrosis factor-alpha (TNF-alpha) and its receptors (TNFR1 and TNFR2) in the spinal cord dorsal horn of rats with partial sciatic nerve transection (PST). METHODS: Male Wistar rats underwent intrathecal catheter implantation for drug delivery and were divided in 7 groups: sham-operated + saline (sham), PST + saline (S), PST + 15 ng naloxone (n), PST + 15 microg naloxone (N), PST + 10 microg morphine (M), PST + 15 ng naloxone + 10 microg morphine (Mn), PST + 15 microg naloxone + 10 microg morphine (MN). Thermal withdrawal latency and mechanical withdrawal threshold, TNF-alpha and TNFR expression in the spinal cord and dorsal root ganglia, and EAAs glutamate and aspartate concentration in cerebrospinal fluid dialysates were measured. RESULTS: Ten days after PST, rats developed hyperalgesia (P < 0.0001) and allodynia (P < 0.0001), and increased TNF-alpha (P < 0.0001) and TNFR1 expression (P = 0.0009) were measured in the ipsilateral spinal cord dorsal horn. The antihyperalgesic and antiallodynic effects of morphine (10 mug) were abolished by high-dose naloxone (15 mug; P = 0.0031) but enhanced by ultra-low dose naloxone (15 ng; P = 0.0015), and this was associated with a reduction of TNF-alpha (P < 0.0001) and TNFR1 (P = 0.0009) expression in the spinal cord dorsal horn and EAAs concentration (glutamate: P = 0.0001; aspartate: P = 0.004) in cerebrospinal fluid dialysate. Analysis of variance (ANOVA) or Student t test with Bonferroni correction were used for statistical analysis. CONCLUSIONS: Ultra-low dose naloxone enhances the antihyperalgesia and antiallodynia effects of morphine in PST rats, possibly by reducing TNF-alpha and TNFR1 expression, and EAAs concentrations in the spinal dorsal horn. Ultra-low dose naloxone may be a useful adjuvant for increasing the analgesic effect of morphine in neuropathic pain conditions.


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RGD Object Information
RGD ID: 8661737
Created: 2014-06-13
Species: All species
Last Modified: 2014-06-13
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.