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Histaminergic Involvement in Neuropathic Pain Produced by Partial Ligation of the Sciatic Nerve in Rats
  1. Liang Huang, M.D.,
  2. Naoto Adachi, M.D., Ph.D.,
  3. Takumi Nagaro, M.D.,
  4. Keyue Liu, M.D. and
  5. Tatsuru Arai, M.D.
  1. Department of Anesthesiology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
  2. Department of Anesthesiology and Resuscitology, Ehime University Graduate School of Medicine, Shitsukawa, Touon-shi, Ehime, Japan.
  1. Reprint requests: Naoto Adachi, M.D., Ph.D., Department of Anesthesiology and Resuscitology, Ehime University Graduate School of Medicine, Shitsukawa, Touon-shi, Ehime 791-0295, Japan. E-mail: nadachi{at}


Background and Objectives: Because the histaminergic system in the brain is involved in regulation of pain, the relationship between central histaminergic activity and neuropathic pain is of interest.

Methods: Neuropathic pain was induced in rats by partial ligation of the left sciatic nerve, and changes in the extracellular concentration of histamine in the right striatum were examined by a microdialysis procedure 2 weeks later. The nociceptive threshold was determined with von Frey tests, and effects of histaminergic ligands were examined.

Results: Although the extracellular concentration of histamine did not differ between the sham-operated and ligated groups, histaminergic activity assessed by metoprine-induced accumulation of histamine was facilitated in ligated animals. The metoprine treatment ameliorated neuropathic pain in ligated animals, although the agent did not affect the threshold in sham-operated rats. Either intracerebroventricular (ICV) administration of histamine (30 μg) or intraperitoneal (IP) administration of l-histidine (370 mg/kg) decreased the nociceptive threshold in ligated rats. However, a high dose of histamine (180 μg ICV) increased the nociceptive threshold. Ranitidine (100 μg ICV), an H2 antagonist, increased the threshold, whereas pyrilamine (15 μg ICV), an H1 antagonist, showed no remarkable change. Administration of thioperamide (30 μg ICV), an H3 antagonist, increased the threshold, although systemic administration of the agent (3.6 mg/kg IP) decreased it.

Conclusions: Blockade of supraspinal histamine H2 receptors or stimulation of spinal H3 receptors may contribute to alleviation of neuropathic pain.

  • Histamine
  • Microdialysis
  • Neuropathic pain
  • Rat
  • Sciatic nerve ligation
  • Striatum

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  • Supported by the Sasagawa Scholarship of Japan, Sasagawa Group.