Fentanyl produces an anti-hyperalgesic effect through the suppression of sodium channels in mice with painful diabetic neuropathy.
Diabetic neuropathy is one of the most frequent complications of diabetes mellitus. Therefore, the present study was designed to investigate the anti-hyperalgesic mechanism of fentanyl in a mouse model of streptozotocin-induced diabetic neuropathy. The antinociceptive response was assessed by recording the latency in a tail-flick test. The tail-flick latency in diabetic mice was significantly shorter than that in non-diabetic mice. Fentanyl, at doses of 3 and 10 μg/kg, s.c., produced a dose-dependent increase in the tail-flick latencies in diabetic mice. While fentanyl (3 μg/kg, s.c.) did not produce a significant inhibition of the tail-flick response in non-diabetic mice, it significantly prolonged the tail-flick latency in diabetic mice to the same level as the baseline latency in non-diabetic mice. Although pretreatment with naloxone (3mg/kg, s.c.) completely antagonized fentanyl-induced antinociception in non-diabetic mice, it had no effect on the antinociceptive effect of fentanyl in diabetic mice. Pretreatment with either of the voltage-gated sodium channel openers fenvarelarte and veratridine practically abolished the antinociceptive effects of fentanyl in diabetic mice. However, neither fenvarelate nor veratridine affected the antinociceptive effect of fentanyl in non-diabetic mice. These results suggest that the anti-hyperalgesic effect of fentanyl is mediated through the blockade of sodium channels in diabetic mice, whereas opioid receptors mediate the antinociceptive effect of fentanyl in non-diabetic mice.
Department of Pathophysiology and Therapeutics, School of Pharmacy and Pharmaceutical Sciences, Hoshi University, 4-41, Ebara 2-Chome, Shinagawa-Ku, Tokyo 142-8501, Japan; Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Japan.
Ken-ichiro
K
Tanaka
Department of Pathophysiology and Therapeutics, School of Pharmacy and Pharmaceutical Sciences, Hoshi University, 4-41, Ebara 2-Chome, Shinagawa-Ku, Tokyo 142-8501, Japan.
Yuki
Y
Nakanishi
Department of Pathophysiology and Therapeutics, School of Pharmacy and Pharmaceutical Sciences, Hoshi University, 4-41, Ebara 2-Chome, Shinagawa-Ku, Tokyo 142-8501, Japan.
Shyota
S
Sekino
Department of Pathophysiology and Therapeutics, School of Pharmacy and Pharmaceutical Sciences, Hoshi University, 4-41, Ebara 2-Chome, Shinagawa-Ku, Tokyo 142-8501, Japan.
Megumi
M
Ikegami
Department of Pathophysiology and Therapeutics, School of Pharmacy and Pharmaceutical Sciences, Hoshi University, 4-41, Ebara 2-Chome, Shinagawa-Ku, Tokyo 142-8501, Japan.
Hiroko
H
Ikeda
Department of Pathophysiology and Therapeutics, School of Pharmacy and Pharmaceutical Sciences, Hoshi University, 4-41, Ebara 2-Chome, Shinagawa-Ku, Tokyo 142-8501, Japan. Electronic address: kamei@hoshi.ac.jp.
Junzo
J
Kamei
D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D003929:Diabetic Neuropathies / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005283:Fentanyl / Q000008:administration & dosage / Q000627:therapeutic use*; D006930:Hyperalgesia / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D008813:Mice, Inbred ICR; D026941:Sodium Channel Blockers / Q000008:administration & dosage / Q000627:therapeutic use*; D015222:Sodium Channels / Q000378:metabolism*; D013311:Streptozocin / Q000494:pharmacology
D000701:Analgesics, Opioid; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D013311:Streptozocin; D005283:Fentanyl
Fentanyl; Mouse; Opioid receptor; Painful diabetic neuropathy; Voltage-gated sodium channel