Tandospirone prevents anesthetic-induced respiratory depression through 5-HT1A receptor activation in rats

Abstract

Respiratory depression is a side effect of anesthetics. Treatment with specific antagonists or respiratory stimulants can reverse respiratory depression caused by anesthetics; however, they also interfere with the sedative effects of anesthetics. Previous studies have suggested that tandospirone may ameliorate respiratory depression without affecting the sedative effects of anesthetics. Therefore, we evaluated whether tandospirone (0.1-8 mg/kg) ameliorates respiratory depression in a rat model under anesthesia. The protein kinase A redistribution method was used to determine whether tandospirone activates α_2a/2c and µ receptors. The effects of tandospirone (10 µM) on α₁β₂γ₂ and α₄β₂δ GABA receptor current modulation were explored by two-electrode voltage clamping. Prophylactic tandospirone administration reduced respiratory depression caused by anesthetics in rats. Tandospirone (0.1-8 mg/kg) increased SaO₂ in rats treated with fentanyl (80 µg/kg) or midazolam (80 mg/kg) (P < 0.05). The ability of tandospirone to prevent respiratory depression was inhibited by the 5-hydroxytryptamine (5-HT)_{1 A} receptor antagonist WAY100635 (1 mg/kg) (P < 0.05). Co-administration of tandospirone with dexmedetomidine or fentanyl did not affect α_2a/2c or µ receptors activation. Tandospirone (10 µM) did not affect α₁β₂γ₂ and α₄β₂δ GABA receptor modulation (P < 0.05). Overall, tandospirone ameliorated respiratory depression caused by anesthetics in rats through 5-HT_1A receptor activation.

Keywords: 5-HT1A; Dexmedetomidine; Fentanyl; Midazolam; Respiratory depression; Tandospirone.

Fig. 1

Pharmacodynamic ability of tandospirone to ameliorate fentanyl-induced respiratory depression and effect of the 5-HT_1A receptor antagonist WAY100635. (a) The rats were administered intravenous tandospirone (0.1, 0.5, 1, 2, 4, or 8 mg/kg) or vehicle and monitored continuously for 60 min at 5-minute intervals after fentanyl injection (80 µg/kg). The data are presented as the mean ± standard error of the mean (n = 5 rats per group) (^ΦP < 0.0001, ^ΩP < 0.001, ^$P < 0.01, ^*P < 0.05 vs. the vehicle control group). (b) Pre-administration of WAY100635 (1 mg/kg) to block tandospirone (4 mg/kg) followed by fentanyl injection showed that WAY100635 completely blocked the ability of tandospirone to reduce respiratory depression. The data are presented as the mean ± standard error of the mean (n = 5 rats per group) (^ΦP < 0.0001, ^ΩP < 0.001, ^$P < 0.01, ^*P < 0.05 vs. the group injected with WAY100635, tandospirone, and fentanyl). (c) The rats were acclimatized for 15 min and then injected with fentanyl (80 µg/kg) to establish the respiratory depression model. Combinations of naloxone (7.5 µg/kg), nikethamide (80 mg/kg), tandospirone (2 or 4 mg/kg), and vehicle were administered 15 min later. Fentanyl-induced respiratory depression was significantly reduced in all but the vehicle control group. The data are presented as the mean ± standard error of the mean (n = 5 rats per group) (^$P < 0.01, ^*P < 0.05 vs. the nikethamide-injected group). 5-HT_1A, 5-hydroxytryptamine; FEN, fentanyl; Nalo, naloxone; Nike, nikethamide; TS, tandospirone.

Fig. 2

Pharmacodynamic ability of tandospirone to ameliorate dexmedetomidine-induced respiratory depression and effect of the 5-HT_1A antagonist WAY100635. (a) The rats in each group were administered intravenous tandospirone (0.5, 1, 2, 4, 8, or 16 mg/kg) or vehicle and continuously monitored for 36 min at 3-minute intervals after dexmedetomidine administration (2 mg/kg). The data are presented as the mean ± standard error of the mean (n = 5–7 rats per group) (^ΦP < 0.0001, ^ΩP < 0.001, ^$P < 0.01, ^*P < 0.05 vs. the vehicle-injected group). (b Pre-administration of WAY100635 (1 mg/kg) to block tandospirone (4 mg/kg) followed by fentanyl injection showed that WAY100635 partially blocked the effects of dexmedetomidine (2 mg/kg), reducing respiratory depression. The data are presented as the mean ± standard error of the mean (n = 5 rats per group) (^ΦP < 0.0001, ^ΩP < 0.001, ^$P < 0.01, ^*P < 0.05 vs. the WAY100635, tandospirone, and dexmedetomidine-injected group). (c) In the dexmedetomidine (2 mg/kg) group, only the specific antagonist atipamezole (1.8 mg/kg) reduced dexmedetomidine-induced respiratory depression, whereas nikethamide (80 mg/kg), tandospirone (2 mg/kg), and vehicle did not. The data are presented as the mean ± standard error of the mean (n = 5 rats per group) (^$P < 0.01, ^*P < 0.05 vs. the nikethamide-injected group). 5-HT_1A, 5-hydroxytryptamine; Atim, atipamezole; DMED, dexmedetomidine; Nike, nikethamide; TS, tandospirone.

Fig. 3

Pharmacodynamic ability of tandospirone to ameliorate midazolam-induced respiratory depression and effects of the 5-HT_1A receptor antagonist WAY100635. (a) The rats were administered tandospirone (2, 4, or 8 mg/kg) or vehicle by intravenous injection and continuously monitored for 36 min at 3-minute intervals after midazolam administration (80 mg/kg). The data are presented as the mean ± standard error of the mean (n = 5 rats per group) (^ΦP < 0.0001, ^ΩP < 0.001, ^$P < 0.01, ^*P < 0.05 vs. the vehicle-injected group). (b) In the group administered midazolam (80 mg/kg), respiratory depression was alleviated by the specific antagonists flumazenil (1.8 mg/kg) and tandospirone (2 mg/kg). Nikethamide and vehicle had no such ameliorative effect. The data are presented as the mean ± standard error of the mean (n = 5 rats per group) (^$P < 0.01, ^*P < 0.05 vs. the nikethamide-injected group). (c) Pre-administration of WAY100635 (1 mg/kg) to block tandospirone (4 mg/kg) followed by midazolam (80 mg/kg) showed that WAY100635 completely blocked midazolam, leading to an improvement in respiratory depression. The data are presented as the mean ± standard error of the mean (n = 5 rats per group) (^ΦP < 0.0001, ^ΩP < 0.001, ^$P < 0.01, ^*P < 0.05 vs. the WAY100635, tandospirone, and midazolam-injected group). 5-HT_1A, 5-hydroxytryptamine; Flu, flumazenil; MID, midazolam; Nike, nikethamide; TS, tandospirone.

Fig. 4

(a) The number of fluorescent particles in the forskolin alone group was markedly decreased in CHO-α_2a/2c-PKAcat-EGFP and CHO-µ-PKAcat-EGFP cells compared with the control group. (ai–bii) Dexmedetomidine activated α_2a/2c receptors on CHO-PKAcat-EGFP cells in a concentration-dependent manner causing significant PKA redistribution. (c i–cii) Fentanyl activated µ receptors on CHO-PKAcat-EGFP cells in a concentration-dependent manner causing significant PKA redistribution. In the tandospirone group, there was no significant difference in the number of fluorescent particles compared with the forskolin group. The tandospirone group (1 × 10^− 5 to 1 × 10^− 9 mol·L^− 1) and the dexmedetomidine/fentanyl group (1 × 10^− 7 mol·L^− 1) demonstrated significant reductions in the number of fluorescent particles compared with the control group. In both the tandospirone group (1 × 10^− 7 to 1 × 10^− 11 mol·L^− 1) and the dexmedetomidine/fentanyl group (1 × 10^− 7 mol·L^− 1), there was no significant difference in the number of fluorescent particles when compared with the forskolin group. DMED, dexmedetomidine; FEN, fentanyl; TS, tandospirone,

Fig. 5

Effect of tandospirone on midazolam-induced currents. (a) Tandospirone (10 µM) reduced 1 µM GABA-mediated inward chloride currents and simultaneously inhibited the enhancement of α₁β₂γ₂ GABA receptor and α₄β₂δ GABA receptor currents by midazolam (i–ii and iii–iv). (b) Rate of α₁β₂γ₂ (i) and α₄β₂δ (ii) GABA receptor current modulation by tandospirone. The data are presented as the mean ± standard error of the mean. BIC, bicuculline; GABA, gamma amino-butyric acid; MID, midazolam.