Korean J Physiol Pharmacol.  2017 Nov;21(6):657-666. 10.4196/kjpp.2017.21.6.657.

The efficacy of combination treatment of gabapentin and electro-acupuncture on paclitaxel-induced neuropathic pain

• Kim MJ
• Lee JH
• Jang JU
• Quan FS
• Kim SK
• Kim W

• KMID: 2395261
• DOI: http://doi.org/10.4196/kjpp.2017.21.6.657

Abstract

Paclitaxel, a chemotherapeutic drug, induces severe peripheral neuropathy. Gabapentin (GBT) is a first line agent used to treat neuropathic pain, and its effect is mediated by spinal noradrenergic and muscarinic cholinergic receptors. Electro-acupuncture (EA) is used for treating various types of pain via its action through spinal opioidergic and noradrenergic receptors. Here, we investigated whether combined treatment of these two agents could exert a synergistic effect on paclitaxel-induced cold and mechanical allodynia, which were assessed by the acetone drop test and von Frey filament assay, respectively. Significant signs of allodynia were observed after four paclitaxel injections (a cumulative dose of 8 mg/kg, i.p.). GBT (3, 30, and 100 mg/kg, i.p.) or EA (ST36, Zusanli) alone produced dose-dependent anti-allodynic effects. The medium and highest doses of GBT (30 and 100 mg/kg) provided a strong analgesic effect, but they induced motor dysfunction in Rota-rod tests. On the contrary, the lowest dose of GBT (3 mg/kg) did not induce motor weakness, but it provided a brief analgesic effect. The combination of the lowest dose of GBT and EA resulted in a greater and longer effect, without inducing motor dysfunction. This effect on mechanical allodynia was blocked by spinal opioidergic (naloxone, 20 μg), or noradrenergic (idazoxan, 10 μg) receptor antagonist, whereas on cold allodynia, only opioidergic receptor antagonist blocked the effect. In conclusion, the combination of the lowest dose of GBT and EA has a robust and enduring analgesic action against paclitaxel-induced neuropathic pain, and it should be considered as an alternative treatment method.

Keyword

Cold allodynia; Electro-acupuncture; Gabapentin; Mechanical allodynia; Paclitaxel

MeSH Terms

Acetone
Hyperalgesia
Methods
Neuralgia*
Paclitaxel
Peripheral Nervous System Diseases
Receptors, Cholinergic
Acetone
Paclitaxel
Receptors, Cholinergic

Figure

• 

  Fig. 1 Elapsed time of cold and mechanical allodynia induced by paclitaxel injections. Behavioral tests for cold and mechanical allodynia were performed before (time point zero) and after four injections of 2 mg/kg paclitaxel (days 0, 2, 4, and 6, i.p., n=10). Also, 1:1 cremophor EL and EtOH diluted in PBS was used as the vehicle (i.p., n=9). Cold (a) and mechanical (b) allodynia assessments were made by the acetone drop test and von Frey filament assay, respectively. Data is presented as mean±S.E.M.; ***p<0.001 vs. vehicle, by Two-way ANOVA.

• 

  Fig. 2 Elapsed time of the dose-dependent effect of GBT on paclitaxel-induced cold and mechanical allodynia in mice. Mice with paclitaxel-induced cold and mechanical allodynia were divided into four groups: PBS (PBS, n=6), GBT 3 mg/kg (GBT3, n=7), GBT 30 mg/kg (GBT30, n=7), and GBT 100 mg/kg (GBT100, n=6). PBS was used as control and both PBS and GBT were administered intraperitoneally. (a) Elapsed time and dose-dependent effect of GBT on cold allodynia. (b) Elapsed time and the dose-dependent effect of GBT on mechanical allodynia. Bl refers to baseline and represent data for behavioral assessments before the injection of paclitaxel. Data is presented as mean±S.E.M.; **p<0.01, ***p<0.001 vs. PBS; by Two-way ANOVA.

• 

  Fig. 3 Elapsed time of the effect of EA and MA on paclitaxel-induced cold and mechanical allodynia in mice. Mice with paclitaxel-induced cold and mechanical allodynia were divided into three groups: CONT (control, n=4), MA (manual acupuncture, ST 36, n=6), EA (electro-acupuncture, ST 36, n=6). (a) Elapsed time of the analgesic effect of EA and MA in cold allodynia-induced mice. (b) Elapsed time of the analgesic effect of EA and MA in mechanical allodynia-induced mice. Bl refers to baseline. Data is presented as mean±S.E.M.; **p<0.01, ***p<0.001 vs. CONT; by Two-way ANOVA.

• 

  Fig. 4 Elapsed time of the synergistic effect of the lowest dose of GBT and EA at ST36. Mice with paclitaxel-induced cold and mechanical allodynia were divided into four groups: CONT (control, n=6), GBT3+MA (GBT 3 mg/kg+MA, n=6), PBS+EA (n=6), GBT3+EA (GBT 3 mg/kg+EA, n=6). Elapsed time of the effect of combination treatment with GBT and EA was observed in both (a) cold and (b) mechanical allodynia induced by paclitaxel. Bl refers to baseline. Data is presented as mean±S.E.M.; *p<0.05, **p<0.01, ***p<0.001 vs. CONT; by Two-way ANOVA.

• 

  Fig. 5 Rota-rod test performed in GBT and EA treated mice. Paclitaxel-induced cold and mechanical allodynic mice were divided into five groups for performing Rota-rod test: PBS (i.p., n=6), GBT3 (GBT 3 mg/kg, i.p., n=8), GBT30 (GBT 30 mg/kg, i.p., n=8), GBT100 (GBT 100 mg/kg, i.p., n=7), and GBT3+EA (GBT 3 mg/kg (i.p.)+EA (ST36), n=6). Rota-rod tests were performed under the condition of 20 rpm speed with a 300 second cut-off time. PBS was used as control. Data is presented as mean±S.E.M.; **p<0.01, ***p<0.001 vs. PBS; by paired t-test.

• 

  Fig. 6 Analgesic mechanism at the spinal level due to the synergistic effect of GBT and EA on paclitaxel-induced allodynia in mice. (a) Effect of naloxone, idazoxan, atropine, and PBS pretreatment on the analgesic effect of GBT and EA on paclitaxel-induced cold allodynia. (b) Effect of naloxone, idazoxan, atropine, and PBS pretreatment on the analgesic effect of GBT and EA on paclitaxel-induced mechanical allodynia. Mice with paclitaxel-induced cold and mechanical allodynia were divided into four groups: PBS (i.t., n=6), Naloxone (20 µg, i.t., n=6), Idazoxan (10 µg, i.t., n=6), and Atropine (0.1 µg , i.t., n=5). Antagonists were injected 20 min prior to GBT and EA treatment, and all behavioral assessments were made 60 min after GBT and EA treatment. Data is presented as mean±S.E.M.; **p<0.01, ***p<0.001 vs. PBS; by paired t-test.

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