title: Intrathecal ultra-low dose naloxone enhances the antihyperalgesic effects of morphine and attenuates tumor necrosis factor-α and tumor necrosis factor-α receptor 1 expression in the dorsal horn of rats with partial sciatic nerve transection.
abstract: 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-α (TNF-α) 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 µg naloxone (N), PST + 10 µg morphine (M), PST + 15 ng naloxone + 10 µg morphine (Mn), PST + 15 µg naloxone + 10 µg morphine (MN). Thermal withdrawal latency and mechanical withdrawal threshold, TNF-α 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-α (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 μg) were abolished by high-dose naloxone (15 μg; P = 0.0031) but enhanced by ultra-low dose naloxone (15 ng; P = 0.0015), and this was associated with a reduction of TNF-α (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-α 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.
authors.affiliation: From the *Division of Anesthesiology, Armed Forces Taoyuan General Hospital, Taoyuan; †Tri-Service General Hospital, ‡Department of Anesthesiology, and §Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei; ‖Division of Mental Health and Addiction Medicine, Institute of Population Health Sciences, National Health Research Institutes, Miaoli County; and ¶Department of Anesthesiology, Cathy General Hospital, Taipei, Taiwan.
authors.forename: Chih-Ping
authors.initials: CP
authors.lastname: Yang
authors.forename: Chen-Hwan
authors.initials: CH
authors.lastname: Cherng
authors.forename: Ching-Tang
authors.initials: CT
authors.lastname: Wu
authors.forename: Hui-Yi
authors.initials: HY
authors.lastname: Huang
authors.forename: Pao-Luh
authors.initials: PL
authors.lastname: Tao
authors.forename: Sing-Ong
authors.initials: SO
authors.lastname: Lee
authors.forename: Chih-Shung
authors.initials: CS
authors.lastname: Wong
mesh_terms: D000701:Analgesics, Opioid / Q000008:administration & dosage*; D000818:Animals; D001224:Aspartic Acid / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects; D004195:Disease Models, Animal; D015536:Down-Regulation; D004357:Drug Synergism; D018698:Glutamic Acid / Q000378:metabolism; D006930:Hyperalgesia / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology / Q000523:psychology; D007278:Injections, Spinal; D008297:Male; D009020:Morphine / Q000008:administration & dosage*; D009270:Naloxone / Q000008:administration & dosage*; D009292:Narcotic Antagonists / Q000008:administration & dosage*; D017288:Pain Threshold / Q000187:drug effects*; D020671:Posterior Horn Cells / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011930:Reaction Time / Q000187:drug effects; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000187:drug effects* / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000187:drug effects / Q000378:metabolism; D012584:Sciatic Nerve / Q000601:surgery; D012585:Sciatica / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology / Q000523:psychology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; C506237:Tnfrsf1a protein, rat; D014409:Tumor Necrosis Factor-alpha; D001224:Aspartic Acid; D009270:Naloxone; D018698:Glutamic Acid; D009020:Morphine