Here, we investigated the mechanism of the antihyperalgesic effect of capsaicin cream in the nerve injury-induced neuropathic pain model in mice. In naive mice, application of capsaicin cream onto footpad caused no significant changes in the thermal latency in contrast to the severe thermal hyperalgesia induced by a capsaicin ointment. On the other hand, application of the cream 3 h before test concentration dependently reversed both thermal and mechanical hyperalgesia observed after partial sciatic nerve injury in mice. In algogenic-induced nociceptive flexion (ANF) test, application of 0.1% capsaicin cream in naive mice blocked intraplantar (i.pl.) nociceptin-and ATP-induced flexion responses, whereas prostaglandin I 2 (PGI 2 ) agonist-induced responses were unaffected. After nerve injury PGI 2 agonist-induced flexion responses were hypersensitized, and capsaicin cream concentration dependently blocked these hyperalgesic responses. Intraplantar injection of capsaicin solution in ANF test also produced potent flexion responses in naive mice that were lost after neonatal capsaicintreatment. Partial sciatic nerve injury in neonatal capsaicintreated mice caused reappearance of i.pl. capsaicin-induced flexion responses, suggesting novel expression of capsaicin receptors due to injury. The PGI 2 agonist-induced responses were also hypersensitized in such injured mice. Capsaicin cream completely reversed both i.pl. capsaicin-or i.pl. PGI 2 agonist-induced hyperalgesia in neonatal capsaicin-treated injured mice. Finally, novel expression of VR1 receptors on neonatal capsaicin-insensitive neurons after nerve injury was confirmed by immunohistochemistry. The newly expressed VR1 receptors after nerve injury were mainly confined to A-fibers. Together, our results suggest that novel expression of capsaicin receptors in neuropathic condition contributes to the analgesic effects of the capsaicin cream.
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 I 2 (PGI 2 ) agonist-induced nociception in such mice. Application of capsaicin cream dose dependently reversed the thermal, mechanical, and PGI 2 agonist-induced hyperalgesia observed in the diabetic mice. The i.pl. injection of capsaicin solution (0.4 g/20 l) 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.Painful peripheral neuropathy is one of the most common complications in early stages of diabetes mellitus. The underlying mechanisms for the development of painful peripheral neuropathy in diabetic patients are poorly understood. Hyperglycemia is considered as a major pathogenic factor in the development of peripheral diabetic neuropathy. In experimental animals, local infusion of glucose into dorsal root ganglion (DRG) or sciatic nerve induced profound and rapid mechanical hyperalgesia (Dobretsov et al., 2001). It is not clear which types of primary afferents are involved in mediating the diabetic neuropathic pain. Hyperactivity of small diameter C-fibers has been suggested in the development of diabetic neuropathic pain (Chen and Levine, 2001). However, in a recent study the development of hyperalgesia could not be prevented in STZ-induced diabetic rats after the systemic pretreatment with resiniferatoxin, which produces long-lasting desensitization of unmyelinated nociceptive C-fibers (Khan et al., 2002). Moreover, ectopic discharges and spontaneous activity were mainly confined to the myelinated A-␦ and A- fibers, but not the C-fibers, in the diabetic rats (Khan et al., 2002). Thus, the myelinated ...
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