Abstract
Topical capsaicin is believed to alleviate pain by desensitizing the vanilloid receptor 1 (VR1) at the peripheral nerve endings. Here, we report that an up-regulation of VR1 expression on myelinated fibers contributes to the antihyperalgesic effect of capsaicin cream in streptozotocin (STZ)-induced diabetic neuropathic pain. Intravenous injection of STZ (200 mg/kg) in mice caused rapid onset of diabetes within 24 h. Thermal and mechanical hyperalgesia developed by 3 days after STZ injection and persisted at all time points tested until 28 days. There was also hyperalgesic response to intraplantar (i.pl.) prostaglandin I2 (PGI2) agonist-induced nociception in such mice. Application of capsaicin cream dose dependently reversed the thermal, mechanical, and PGI2 agonist-induced hyperalgesia observed in the diabetic mice. The i.pl. injection of capsaicin solution (0.4 μg/20 μl) produced nociceptive biting-licking responses in control mice, and these responses were significantly increased in STZ-induced diabetic mice. After neonatal capsaicin-treatment, which destroys most unmyelinated C-fibers, the i.pl. capsaicin-induced biting-licking responses were almost abolished. However, in neonatal capsaicin-treated diabetic mice, the i.pl. capsaicin-induced biting-licking responses reappeared. The i.pl. capsaicin-induced biting-licking responses were blocked by the competitive VR1 antagonist capsazepine. All these results suggest an increase in capsaicin receptor on myelinated fibers due to diabetes. Finally, we confirmed the up-regulation of VR1 expression on myelinated primary afferent neurons of diabetic mice by immunohistochemistry. Together, our results suggest that increased expression of VR1 on myelinated fibers might contribute to the antihyperalgesic effect of topical capsaicin in diabetic neuropathic pain.
Footnotes
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This study was supported in part by Special Coordination Funds of the Science and Technology Agency of the Japanese Government, a Research Grant from Environmental Agency, Government of Japan, grants-in-aid from the Ministry of Education, Science, Culture, and Sports of Japan and a grant for Human Frontier Science Program.
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DOI: 10.1124/jpet.103.050948.
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ABBREVIATIONS: DRG, dorsal root ganglion; VR1, vanilloid receptor 1; SP, substance P; CPZ, capsazepine; PGI2, prostaglandin I2; STZ, streptozotocin; ANF, algogenic-induced nociceptive flexion; i.pl., intraplantar; ONO-54918-07, 15-cis-(4-n-propylcyclohexyl)-16,17,18,19,20-pentanor-9-deoxy-6,9-α-nitriloprostaglandin F1; PBS, phosphate-buffered saline; RT, room temperature; ANOVA, analysis of variance.
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↵1 M.H.R. and M.I. contributed equally to this work.
- Received February 25, 2003.
- Accepted April 22, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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