Korean J Physiol Pharmacol.  2018 May;22(3):331-341. 10.4196/kjpp.2018.22.3.331.

Preemptive application of QX-314 attenuates trigeminal neuropathic mechanical allodynia in rats

• Yoon JH
• Son JY
• Kim MJ
• Kang SH
• Ju JS
• Bae YC
• Ahn DK

• KMID: 2410097
• DOI: http://doi.org/10.4196/kjpp.2018.22.3.331

Abstract

The aim of the present study was to examine the effects of preemptive analgesia on the development of trigeminal neuropathic pain. For this purpose, mechanical allodynia was evaluated in male Sprague-Dawley rats using chronic constriction injury of the infraorbital nerve (CCI-ION) and perineural application of 2% QX-314 to the infraorbital nerve. CCI-ION produced severe mechanical allodynia, which was maintained until postoperative day (POD) 30. An immediate single application of 2% QX-314 to the infraorbital nerve following CCI-ION significantly reduced neuropathic mechanical allodynia. Immediate double application of QX-314 produced a greater attenuation of mechanical allodynia than a single application of QX-314. Immediate double application of 2% QX-314 reduced the CCI-ION-induced upregulation of GFAP and p-p38 expression in the trigeminal ganglion. The upregulated p-p38 expression was co-localized with NeuN, a neuronal cell marker. We also investigated the role of voltage-gated sodium channels (Navs) in the antinociception produced by preemptive application of QX-314 through analysis of the changes in Nav expression in the trigeminal ganglion following CCI-ION. Preemptive application of QX-314 significantly reduced the upregulation of Nav1.3, 1.7, and 1.9 produced by CCI-ION. These results suggest that long-lasting blockade of the transmission of pain signaling inhibits the development of neuropathic pain through the regulation of Nav isoform expression in the trigeminal ganglion. Importantly, these results provide a potential preemptive therapeutic strategy for the treatment of neuropathic pain after nerve injury.

Keyword

Mechanical allodynia; Preemptive analgesia; QX-314; Sodium channel; Trigeminal neuropathic pain

MeSH Terms

Analgesia
Animals
Constriction
Humans
Hyperalgesia*
Male
Neuralgia
Neurons
Rats*
Rats, Sprague-Dawley
Sodium Channels
Trigeminal Ganglion
Up-Regulation
Voltage-Gated Sodium Channels
Sodium Channels
Voltage-Gated Sodium Channels

Figure

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  Fig. 1 The effects of a single application of 2% QX-314 on neuropathic mechanical allodynia in rats with chronic constriction injury of the infraorbital nerve (CCI-ION).CCI-ION produced significantly mechanical allodynia. Treatment with vehicle did not alter the CCI-ION-induced mechanical allodynia. Perineural application of QX-314 immediately following CCI-ION significantly reduced neuropathic mechanical allodynia. Combined treatment with capsaicin (1 mg) produced attenuation of neuropathic mechanical allodynia. However, the anti-allodynic effects following treatment with QX-314 in combination with capsaicin did not differ from these effects following treatment with QX-314 alone. Arrow, single application of QX-314. There were 8 animals in each group. *p<0.05, vehicle- vs. QX-314- or cap+QX-314-treated group.

• 

  Fig. 2 The effects of immediate double application of 2% QX-314 on CCI-ION-induced mechanical allodynia.Perineural double application of QX-314 immediately following CCI-ION significantly attenuated neuropathic mechanical allodynia compared with the effects of a single application of QX-314. Arrow, double application of QX-314. There were 8 animals in each group. *p<0.05, vehicle- vs. QX-314 (single)-treated group. #p<0.05, QX-314 (single)- vs. QX-314 (double)-treated group.

• 

  Fig. 3 The effects of 2% QX-314 on CCI-ION-induced mechanical allodynia on POD 7.Single or double application of QX-314 did not affect neuropathic mechanical allodynia when pain was already established. Arrow, application of QX-314 on POD 7. There were 8 animals in each group.

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  Fig. 4 The effects of immediate double application of 2% QX-314 on the concentration of extravasated Evans blue dye in rats following CCI-ION.CCI-ION produced a significant increase in the extravasated Evans blue dye concentration. However, QX-314-induced preemptive analgesia did not affect the extravasated Evans blue dye concentration. *p<0.05, sham vs. vehicle+CCI-ION group. There were 6 animals in each group.

• 

  Fig. 5 The effect of immediate double application of 2% QX-314 on the expression of ATF-3, a neuronal injury marker, in rats following CCI-ION.CCI-ION significantly increased the number of ATF-3-immunoreactive cells in the trigeminal ganglion. However, application of QX-314 did not affect the number of cells with ATF-3 immunoreactivity following CCI-ION. Scale bar, 200 µm.

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  Fig. 6 The effects of immediate double application of 2% QX-314 on GFAP and p-p38 expression in the trigeminal ganglion.(A) CCI-ION upregulated GFAP and p-p38 expression on POD 7. Double application of QX-314 reduced the GFAP and p-p38 upregulation in the trigeminal ganglion following CCI-ION. Scale bar, 200 µm. (B, C) CCI-ION increases the area density of GFAP and p-p38 immunoreactivity compared to the immunoreactivity observed in the sham group. Treatment with QX-314 significantly decreases the upregulated area density of GFAP and p-p38 immunoreactivity. *p<0.05, sham vs. CCI-ION group. #p<0.05, CCI-ION vs. QX-314+CCI-ION groups.

• 

  Fig. 7 Double immunostaining for p-p38 with NeuN (a marker of neuron) and GFAP (a marker of satellite cell) to determine the localization of p-p38 in the trigeminal ganglion.The double immunofluorescence signals revealed a co-localization of p-p38 with NeuN but not with GFAP. Scale bar, 100 µm.

• 

  Fig. 8 The effects of preemptive analgesia on the expression of Navs1.3, 1.7, 1.8, and 1.9 in the trigeminal ganglion.CCI-ION significantly increased the expression of Nav1.3, 1.7, and 1.9 on POD 7 but did not affect the expression of Nav1.8. QX-314-induced preemptive analgesia significantly reduced the Nav1.3, 1.7, and 1.9 upregulation observed in rats following CCI-ION. GAPDH was used as an internal control. *p<0.05, naive vs. CCI-ION group. #p<0.05, CCI-ION vs. QX-314+CCI-ION groups. There were 6 animals in each group.

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