Korean J Physiol Pharmacol.  2015 Jul;19(4):349-355. 10.4196/kjpp.2015.19.4.349.

Antinociceptive Effects of Transcytosed Botulinum Neurotoxin Type A on Trigeminal Nociception in Rats

• Kim HJ
• Lee GW
• Kim MJ
• Yang KY
• Kim ST
• Bae YC
• Ahn DK

• KMID: 2285578
• DOI: http://doi.org/10.4196/kjpp.2015.19.4.349

Abstract

We examined the effects of peripherally or centrally administered botulinum neurotoxin type A (BoNT-A) on orofacial inflammatory pain to evaluate the antinociceptive effect of BoNT-A and its underlying mechanisms. The experiments were carried out on male Sprague-Dawley rats. Subcutaneous (3 U/kg) or intracisternal (0.3 or 1 U/kg) administration of BoNT-A significantly inhibited the formalin-induced nociceptive response in the second phase. Both subcutaneous (1 or 3 U/kg) and intracisternal (0.3 or 1 U/kg) injection of BoNT-A increased the latency of head withdrawal response in the complete Freund's adjuvant (CFA)-treated rats. Intracisternal administration of N-methyl-D-aspartate (NMDA) evoked nociceptive behavior via the activation of trigeminal neurons, which was attenuated by the subcutaneous or intracisternal injection of BoNT-A. Intracisternal injection of NMDA up-regulated c-Fos expression in the trigeminal neurons of the medullary dorsal horn. Subcutaneous (3 U/kg) or intracisternal (1 U/kg) administration of BoNT-A significantly reduced the number of c-Fos immunoreactive neurons in the NMDA-treated rats. These results suggest that the central antinociceptive effects the peripherally or centrally administered BoNT-A are mediated by transcytosed BoNT-A or direct inhibition of trigeminal neurons. Our data suggest that central targets of BoNT-A might provide a new therapeutic tool for the treatment of orofacial chronic pain conditions.

Keyword

BoNT-A; NMDA; Pain; Transcytosed; Trigeminal

MeSH Terms

Animals
Chronic Pain
Freund's Adjuvant
Head
Horns
Humans
Male
N-Methylaspartate
Neurons
Nociception*
Rats*
Rats, Sprague-Dawley
Freund's Adjuvant
N-Methylaspartate

Figure

• 

  Fig. 1 Effects of the subcutaneous (A) or intracisternal (B) injection of botulinum neurotoxin type A (BoNT-A) on the formalin-induced nociceptive behavior. Subcutaneous injection (1 or 3 U/kg) and intracisternal (0.3 or 1 U/kg) administration of BoNT-A attenuated the formalin-induced nociceptive behavior in the second phase. *p<0.05 vehicle vs. BoNT-A treated group, n=8 animals per group.

• 

  Fig. 2 Effects of the subcutaneous (A) or intracisternal (B) injection of botulinum neurotoxin type A (BoNT-A) on the complete Freund's adjuvant (CFA)-induced thermal hypersensitivity. Both subcutaneous and intracisternal injection of BoNT-A attenuated the head withdrawal latency induced by CFA injection. *p<0.05 vehicle vs. BoNT-A treated group, n=8 animals per group.

• 

  Fig. 3 Effects of the subcutaneous (A) or intracisternal (B) injection of botulinum neurotoxin type A (BoNT-A) on the NMDA-induced nociceptive behavior. Intracisternal administration of 0.5 µg NMDA evoked a significant nociceptive behavior by the activation of trigeminal neurons. Both subcutaneous and intracisternal injections of BoNT-A attenuated the number of rubbing induced by the intracisternal injection of NMDA. *p<0.05 vehicle vs. BoNT-A treated group, n=8 animals per group.

• 

  Fig. 4 Effects of the subcutaneous or intracisternal injection of botulinum neurotoxin type A (BoNT-A) on c-Fos expression in the medullary dorsal horn. (A) c-Fos immunoreactive neurons in a naïve animal. (B) Intracisternal administration of 0.5 µg NMDA increased the number of c-Fos immunoreactive neurons in the superficial lamina I and II in the medullary dorsal horn. (C) Subcutaneous administration of BoNT-A (3 U/kg) decreased the number of c-Fos immunoreactive neurons. (D) Intracisternal injection of BoNT-A (1 U/kg) decreased the number of c-Fos immunoreactive neurons. (E) The histogram shows the number of c-Fos immunoreactive neurons in the ipsilateral medullary dorsal horn. *p<0.05 vehicle vs. BoNT-A treated group, n=5 animals per group. Scale bar, 100 µm.

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