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[Xylazine Produced Analgesic Effect via Inhibits Hyperpolarization-activated Cyclic Nucleotide-gated Ion Channels Currents].
Sichuan Da Xue Xue Bao Yi Xue Ban. 2019 Jan; 50(1):20-26.SD

Abstract

OBJECTIVE

To investigate the analgesic mechanism of xylazine by inhibiting the activation of hyperpolarized cyclic nucleotide-gated (HCN) ion channels.

METHODS

HCN subchannel 1 (HCN1) knockout mice (HCN1-/-) and HCN1 wild type mice (HCN1+/+) were intraperitoneally injected with physiological saline and xylazine (10, 20, 30, and 40 mg/kg). Mechanical pain test and tail flick test were used to test the analgesic effect of xylazine by using the percentage of the maximal possible effect (%MPE); The control group and test groups of different concentrations of xylazine (12.5, 25, 50, and 100 μmol/L) were set up using HEK 293 cells transfected HCN1 plasmid and HCN subchannel 2 (HCN2) plasmid, respectively. The activated current of hyperpolarized HEK 293 cells expressing HCN1 and HCN2 ion channels and the inhibition rate of xylazine on hyperpolarization-activated currents were recorded using a whole cell patch clamp.

RESULTS

The results demonstrated that %MPE of the mechanical pain stimuli test and the thermal radiation stimuli test increased with the higher concentration of xylazine injected for both HCN1+/+ mice and HCN1-/-mice. When injecting xylazine by 30 mg/kg and 40 mg/kg, the %MPE of mechanical pain stimuli test for HCN1-/- mice were %MPE= (62.06±14.72) % and %MPE= (69.92±16.09) %, respectively; and the percentages of tail flick tests were (52.50±1.97) % and %MPE= (64.74±6.34) %, respectively. But for HCN1+/+ mice, the percentages of mechanical pain stimuli test were %MPE= (75.47±8.06) % and %MPE= (86.35±11.31) %; respectively, and the percentage of tail flick tests were %MPE= (57.83±4.82) % and (74.98±9.35) %. The analgesic effect results of the mechanical pain test and tail flick test of HCN1+/+ mice were significantly different from HCN1-/- mice (P<0.05). Whole-cell patch clamp test results showed that xylazine had inhibitory effects on the currents of HCN1 and HCN2 ion channels, and the hyperpolarization-activated currents inhibition rate of HCN1 by xylazine (12.5-100 μmol/L) was between (24.62±23.62) %- (62.40±15.48) %; V1/2 of HCN1 was between (-79.58±1.56) mV- (-98.95±3.57) mV. The Ih inhibition rate of HCN2 by xylazine (12.5-100 μmol/L) was between (29.19±17.82) %- (80.02±6.64) %; with V1/2 of HCN2 between (-102.17±1.36) mV- (-117.48±2.38) mV.

CONCLUSION

Xylazine showed better analgesic effect on HCN1+/+ mice than HCN1-/- mice. Xylazine can produce analgesic effect by inhibiting HCN ion channel currents.

Authors+Show Affiliations

Huaxi MR Research Center (HMRRC), West China Hospital, Sichuan University, Chengdu 610041, China.Huaxi MR Research Center (HMRRC), West China Hospital, Sichuan University, Chengdu 610041, China.Department of Anesthesiology, Institute of Anesthesiology and Critical Care Medicine, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.Laboratory of Anesthesia and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu 610041, China.Laboratory of Anesthesia and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu 610041, China.

Pub Type(s)

Journal Article

Language

chi

PubMed ID

31037900

Citation

Chen, Feng-Feng, et al. "[Xylazine Produced Analgesic Effect Via Inhibits Hyperpolarization-activated Cyclic Nucleotide-gated Ion Channels Currents]." Sichuan Da Xue Xue Bao. Yi Xue Ban = Journal of Sichuan University. Medical Science Edition, vol. 50, no. 1, 2019, pp. 20-26.
Chen FF, Li L, Chen XD, et al. [Xylazine Produced Analgesic Effect via Inhibits Hyperpolarization-activated Cyclic Nucleotide-gated Ion Channels Currents]. Sichuan Da Xue Xue Bao Yi Xue Ban. 2019;50(1):20-26.
Chen, F. F., Li, L., Chen, X. D., Zhou, C., & Liao, D. Q. (2019). [Xylazine Produced Analgesic Effect via Inhibits Hyperpolarization-activated Cyclic Nucleotide-gated Ion Channels Currents]. Sichuan Da Xue Xue Bao. Yi Xue Ban = Journal of Sichuan University. Medical Science Edition, 50(1), 20-26.
Chen FF, et al. [Xylazine Produced Analgesic Effect Via Inhibits Hyperpolarization-activated Cyclic Nucleotide-gated Ion Channels Currents]. Sichuan Da Xue Xue Bao Yi Xue Ban. 2019;50(1):20-26. PubMed PMID: 31037900.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - [Xylazine Produced Analgesic Effect via Inhibits Hyperpolarization-activated Cyclic Nucleotide-gated Ion Channels Currents]. AU - Chen,Feng-Feng, AU - Li,Lei, AU - Chen,Xiang-Dong, AU - Zhou,Cheng, AU - Liao,Da-Qing, PY - 2019/5/1/entrez PY - 2019/5/1/pubmed PY - 2019/8/16/medline KW - Analgesia KW - Hyperpolarization-activated cyclic nucleotide-gated ion channels KW - Xylazine KW - α2-adrenergic receptor agonist SP - 20 EP - 26 JF - Sichuan da xue xue bao. Yi xue ban = Journal of Sichuan University. Medical science edition JO - Sichuan Da Xue Xue Bao Yi Xue Ban VL - 50 IS - 1 N2 - OBJECTIVE: To investigate the analgesic mechanism of xylazine by inhibiting the activation of hyperpolarized cyclic nucleotide-gated (HCN) ion channels. METHODS: HCN subchannel 1 (HCN1) knockout mice (HCN1-/-) and HCN1 wild type mice (HCN1+/+) were intraperitoneally injected with physiological saline and xylazine (10, 20, 30, and 40 mg/kg). Mechanical pain test and tail flick test were used to test the analgesic effect of xylazine by using the percentage of the maximal possible effect (%MPE); The control group and test groups of different concentrations of xylazine (12.5, 25, 50, and 100 μmol/L) were set up using HEK 293 cells transfected HCN1 plasmid and HCN subchannel 2 (HCN2) plasmid, respectively. The activated current of hyperpolarized HEK 293 cells expressing HCN1 and HCN2 ion channels and the inhibition rate of xylazine on hyperpolarization-activated currents were recorded using a whole cell patch clamp. RESULTS: The results demonstrated that %MPE of the mechanical pain stimuli test and the thermal radiation stimuli test increased with the higher concentration of xylazine injected for both HCN1+/+ mice and HCN1-/-mice. When injecting xylazine by 30 mg/kg and 40 mg/kg, the %MPE of mechanical pain stimuli test for HCN1-/- mice were %MPE= (62.06±14.72) % and %MPE= (69.92±16.09) %, respectively; and the percentages of tail flick tests were (52.50±1.97) % and %MPE= (64.74±6.34) %, respectively. But for HCN1+/+ mice, the percentages of mechanical pain stimuli test were %MPE= (75.47±8.06) % and %MPE= (86.35±11.31) %; respectively, and the percentage of tail flick tests were %MPE= (57.83±4.82) % and (74.98±9.35) %. The analgesic effect results of the mechanical pain test and tail flick test of HCN1+/+ mice were significantly different from HCN1-/- mice (P<0.05). Whole-cell patch clamp test results showed that xylazine had inhibitory effects on the currents of HCN1 and HCN2 ion channels, and the hyperpolarization-activated currents inhibition rate of HCN1 by xylazine (12.5-100 μmol/L) was between (24.62±23.62) %- (62.40±15.48) %; V1/2 of HCN1 was between (-79.58±1.56) mV- (-98.95±3.57) mV. The Ih inhibition rate of HCN2 by xylazine (12.5-100 μmol/L) was between (29.19±17.82) %- (80.02±6.64) %; with V1/2 of HCN2 between (-102.17±1.36) mV- (-117.48±2.38) mV. CONCLUSION: Xylazine showed better analgesic effect on HCN1+/+ mice than HCN1-/- mice. Xylazine can produce analgesic effect by inhibiting HCN ion channel currents. SN - 1672-173X UR - https://www.unboundmedicine.com/medline/citation/31037900/[Xylazine_Produced_Analgesic_Effect_via_Inhibits_Hyperpolarization_activated_Cyclic_Nucleotide_gated_Ion_Channels_Currents]_ DB - PRIME DP - Unbound Medicine ER -