Peripherally Administered Botulinum Toxin Type A Localizes Bilaterally in Trigeminal Ganglia of Animal Model.

Arief Waskitho,Tsuyoshi Morita,Resmi Raju,Otto Baba,Kazuo Okura,Daisuke Ikutame,Huijiao Yan,Akihito Yamamoto,Yumiko Yamamoto,Fumiya Kano,Swarnalakshmi Raman,Yoshizo Matsuka,Shaista Afroz,Masamitsu Oshima

doi:10.3390/toxins13100704

Abstract

Peripheral nerve injury leads to sensory ganglion hyperexcitation, which increases neurotransmitter release and neuropathic pain. Botulinum toxin type A (BoNT/A) regulates pain transmission by reducing neurotransmitter release, thereby attenuating neuropathic pain. Despite multiple studies on the use of BoNT/A for managing neuropathic pain in the orofacial region, its exact mechanism of transport remains unclear. In this study, we investigated the effects of BoNT/A in managing neuropathic pain in two different animal models and its transport mechanism in the trigeminal nerve. Intraperitoneal administration of cisplatin induced bilateral neuropathic pain in the orofacial region, reducing the head withdrawal threshold to mechanical stimulation. Unilateral infraorbital nerve constriction (IONC) also reduced the ipsilateral head withdrawal threshold to mechanical stimulation. Unilateral peripheral administration of BoNT/A to the rat whisker pad attenuated cisplatin-induced pain behavior bilaterally. Furthermore, contralateral peripheral administration of BoNT/A attenuated neuropathy-induced behavior caused by IONC. We also noted the presence of BoNT/A in the blood using the mouse bioassay. In addition, the Alexa Fluor-488-labeled C-terminal half of the heavy chain of BoNT/A (BoNT/A-Hc) was localized in the neurons of the bilateral trigeminal ganglia following its unilateral administration. These findings suggest that axonal and hematogenous transport are involved in the therapeutic effects of peripherally administered BoNT/A in the orofacial region.

Highlights

Nerve injury in the orofacial region— involving the trigeminal nerve—instigates prolonged pain throughout the surrounding area [1]
Previous studies on the application of botulinum neurotoxin type A (BoNT/A) have demonstrated its effectiveness in reducing neuropathy-induced behavior, which indicates that neurotransmitter release in the sensory ganglia is involved in the regulation of pain transmission [6,7,8]
Our findings suggest that approximately 18% of the intradermally injected Botulinum neurotoxin (BoNT)/A in the rat whisker pad was transported to the bloodstream

Summary

Introduction

Nerve injury in the orofacial region— involving the trigeminal nerve—instigates prolonged pain throughout the surrounding area [1]. Nerve injury in the orofacial region— involving the trigeminal nerve—. The interactions between peripheral and central mechanisms are responsible for the persistence of pain linked with the trigeminal nerve [1]. Peripheral nerve injury leads to neuropathic pain and sensory ganglion hyperexcitation [2]. Previous studies have reported that the hyperexcitation of sensory ganglion neurons increases neurotransmitter release [3,4,5]. Previous studies on the application of botulinum neurotoxin type A (BoNT/A) have demonstrated its effectiveness in reducing neuropathy-induced behavior, which indicates that neurotransmitter release in the sensory ganglia is involved in the regulation of pain transmission [6,7,8]. In the management of neurological disorders, the most widely used type is BoNT/A because it has long-lasting effects [9]. The structure of BoNT is made up of polypeptide chains; namely, a light (L) chain (50 kDa) and a heavy (H)

Methods

Results

Discussion

Conclusion