Analgesic effects of dexmedetomidine in vincristine-evoked painful neuropathic rats

Abstract

Dexmedetomidine, which is a selective α2-adrenoceptor agonist, was recently introduced into clinical practice for its analgesic properties. The purpose of this study was to evaluate the effects of dexmedetomidine in a vincristine-evoked neuropathic rat models. Sprague-Dawley rats were injected intraperitoneally with vincristine or saline (0.1 mg/kg/day) using a 5-day-on, 2-day-off schedule for 2 weeks. Saline and dexmedetomidine (12.5, 25, 50, and 100 µg/kg) were injected to rats developed allodynia 14 days after vincristine injection, respectively. We evaluated allodynia at before, 15, 30, 60, 90, 120, 180, and 240 min, and 24 hr after intraperitoneal drug (normal saline or dexmedetomidine) injection. Saline treatment did not show any differences for all the allodynia. Maximal paw withdrawal thresholds to mechanical stimuli were 3.0 ± 0.4, 9.1 ± 1.9, 13.0 ± 3.6, 16.6 ± 2.4, and 24.4 ± 1.6 g at saline, 12.5, 25, 50, and 100 µg/kg dexmedetomidine injection, respectively. Minimal withdrawal frequency to cold stimuli were 73.3 ± 4.2, 57.1 ± 6.8, 34.3 ± 5.7, 20.0 ± 6.2, and 14.3 ± 9.5 g at saline, 12.5, 25, 50, and 100 µg/kg dexmedetomidine injection, respectively. Dexmedetomidine shows a dose-dependent antiallodynic effect on mechanical and cold stimuli in vincristine-evoked neuropathic rat models (P < 0.05).

Keywords: Dexmedetomidine; Neuropathy; Pain; Vincristine.

Fig. 1

Changes of withdrawal responses during vincristine treatment. (A) Mechanical allodynia. (B) Cold allodynia. (C) Heat hyperalgesia. Results are presented as mean ± standard error of mean (n = 11 in vincristine group, n = 5 in saline group) (^*P < 0.01 vs saline; ^†P < 0.001 vs saline).

Fig. 2

Dexmedetomidine affects mechanical allodynia of vincristine treated rats. (A) The withdrawal threshold to mechanical stimuli in the vincristine-induced neuropathic rats. The withdrawal threshold was observed before (Pre) and after injection of normal saline (NS), dexmedetomidine 12.5 µg/kg (DEX12.5), dexmedetomidine 25 µg/kg (DEX25), dexmedetomidine 50 µg/kg (DEX50), dexmedetomidine 100 µg/kg (DEX100). Results are presented as mean ± standard error of mean (n = 6 in saline group, n = 7 per each dexmedetomidine group) (^*P < 0.05 vs NS; ^†P < 0.01 vs NS; ^‡P < 0.001 vs NS). (B) Dose-response curve of the percentage maximum possible effect (%MPE) on mechanical analgesia in the dexmedetomidine groups. This shows a mechanical analgesia dose-dependently. Each point is represented the mean ± standard error of mean (n = 6 in saline group, n = 7 per each dexmedetomidine group) (^*P < 0.05 vs NS; ^†P < 0.05 vs 12.5 µg/kg; ^‡P < 0.05 vs 25 µg/kg; ^§P < 0.05 vs 50 µg/kg of dexmedetomidine).

Fig. 3

Dexmedetomidine reverses cold allodynia of vincristine treated rats. (A) The withdrawal frequency to cold stimuli. The frequency was measured before (Pre) and after injection of normal saline (NS), dexmedetomidine 12.5 µg/kg (DEX12.5), dexmedetomidine 25 µg/kg (DEX25), dexmedetomidine 50 µg/kg (DEX50), dexmedetomidine 100 µg/kg (DEX100). Results are presented as mean ± standard error of mean (n = 6 in saline group, n = 7 per each dexmedetomidine group) (^*P < 0.05 vs NS; ^†P < 0.01 vs NS; ^‡P < 0.001 vs NS). (B) Dose-response curve of the percentage maximum possible effect (%MPE) on cold analgesia in the dexmedetomidine groups. This shows a cold analgesia dose-dependently. Each point is represented the mean ± standard error of mean (n = 6 in saline group, n = 7 per each dexmedetomidine group) (^*P < 0.05 vs NS; ^†P < 0.05 vs 12.5 µg/kg; ^‡P < 0.05 vs 25 µg/kg of dexmedetomidine).

Fig. 4

The rotarod time of dexmedetomidine-injected rats. Rotarod time was observed before (Pre) and after dexmedetomidine or saline injection. Rotarod time was not decreased by injection of normal saline (NS) and 12.5, 25, and 50 µg/kg of dexmedetomidine. Only 100 µg/kg of dexmedetomidine decreased rotarod time at from 30 to 90 min. Results are presented as mean ± standard error of mean (n = 6 in saline group, n = 7 per each dexmedetomidine group) (^*P < 0.001 vs NS).