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Intrathecal Ultra-Low Dose Naloxone Enhances the Antihyperalgesic Effects of Morphine and Attenuates Tumor Necrosis Factor-a and Tumor Necrosis Factor-a Receptor 1 Expression in the Dorsal Horn of Rats with Partial Sciatic Nerve Transection

Yang, Chih-Ping MD*; Cherng, Chen-Hwan MD, DMSc; Wu, Ching-Tang MD; Huang, Hui-Yi MS§; Tao, Pao-Luh PhD; Lee, Sing-Ong MD; Wong, Chih-Shung MD, PhD§

doi: 10.1213/ANE.0000000000000020
Pain and Analgesic Mechanisms: Research Report

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.

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.

Chih-Ping Yang, MD, is currently affiliated with Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan; and Chih-Shung Wong, MD, PhD, is currently affiliated with Department of Anesthesiology, Cathay General Hospital, Taipei, Taiwan.

Accepted for publication September 23, 2013.

Funding: This study was supported by research grants from the Taoyuan Armed Forces General Hospital, Taoyuan, Taiwan (AFTYGH-10107).

The authors declare no conflicts of interest.

Reprints will not be available from the authors.

Address correspondence to Chih-Shung Wong, MD, PhD, Department of Anesthesiology, Cathay General Hospital, No. 280, Renai Rd., Section 4, Taipei, Taiwan. Address e-mail to

© 2013 International Anesthesia Research Society