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

Affiliations
  • 1Department of Oral Physiology, School of Dentistry, Kyungpook National University, Daegu 700-412, Korea. dkahn@knu.ac.kr
  • 2Department of Oral Anatomy, School of Dentistry, Kyungpook National University, Daegu 700-412, Korea.
  • 3Department of Orofacial Pain and Oral Medicine, School of Dentistry, Yonsei University, Seoul 110-749, Korea.

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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Korean J Physiol Pharmacol. 2018;22(5):539-546.    doi: 10.4196/kjpp.2018.22.5.539.

Participation of central GABAA receptors in the trigeminal processing of mechanical allodynia in rats
Min Ji Kim, Young Hong Park, Kui Ye Yang, Jin Sook Ju, Yong Chul Bae, Seong Kyu Han, Dong Kuk Ahn
Korean J Physiol Pharmacol. 2017;21(1):65-74.    doi: 10.4196/kjpp.2017.21.1.65.


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