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University of Maryland Baltimore

Pharmacol. Ther. , Available online 22 May 2024 | https://doi.org/10.1016/j.pharmthera.2024.108668 Neurobiological mechanisms of botulinum neurotoxin-induced analgesia for neuropathic pain

Ana Bagues^a,b, Jiaxin Hu ^c, Ishraq Alshanqiti ^c,d,e, Man-Kyo Chung ^c,d,f

^aÁrea de Farmacología, Nutrición y Bromatología, Dpto. C.C. Básicas de la Salud, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos, Unidad Asociada I+D+i al Instituto de Química Médica (CSIC), Alcorcón, Spain

^bHigh Performance Research Group in Experimental Pharmacology (PHARMAKOM), Spain

^cDepartment of Neural and Pain Sciences, School of Dentistry, University of Maryland Baltimore, Baltimore, MD 21201, USA

^dProgram in Dental Biomedical Sciences, University of Maryland Baltimore, School of Dentistry, Baltimore, MD 21201, USA

^eDepartment of Basic and Clinical Sciences, School of Dentistry, Umm Al-Qura University, Makkah 24382, Kingdom of Saudi Arabia

^fCenter to Advance Chronic Pain Research, University of Maryland Baltimore, Baltimore, MD 21201, USA

Corresponding author : Man-Kyo Chung

Abstract

Botulinum neurotoxins (BoNTs) are a family of neurotoxins produced by Clostridia and other bacteria that induce botulism. BoNTs are internalized into nerve terminals at the site of injection and cleave soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins to inhibit the vesicular release of neurotransmitters. BoNTs have been approved for multiple therapeutic applications, including the treatment of migraines. They have also shown efficacies for treating neuropathic pain, such as diabetic neuropathy, and postherpetic and trigeminal neuralgia. However, the mechanisms underlying BoNT-induced analgesia are not well understood. Peripherally administered BoNT is taken up by the nerve terminals and reduces the release of glutamate, calcitonin gene-related peptide, and substance P, which decreases neurogenic inflammation in the periphery. BoNT is retrogradely transported to sensory ganglia and central terminals in a microtubule-dependent manner. BoNTs decrease the expression of pronociceptive genes (ion channels or cytokines) from sensory ganglia and the release of neurotransmitters and neuropeptides from primary afferent central terminals, which likely leads to decreased central sensitization in the dorsal horn of the spinal cord or trigeminal nucleus. BoNT-induced analgesia is abolished after capsaicin-induced denervation of transient receptor potential vanilloid 1 (TRPV1)-expressing afferents or the knockout of substance P or the neurokinin-1 receptor. Although peripheral administration of BoNT leads to changes in the central nervous system (e.g., decreased phosphorylation of glutamate receptors in second-order neurons, reduced activation of microglia, contralateral localization, and cortical reorganization), whether such changes are secondary to changes in primary afferents or directly mediated by trans-synaptic, transcytotic, or the hematogenous transport of BoNT is controversial. To enhance their therapeutic potential, BoNTs engineered for specific targeting of nociceptive pathways have been developed to treat chronic pain. Further mechanistic studies on BoNT-induced analgesia can enhance the application of native or engineered BoNTs for neuropathic pain treatment with improved safety and efficacy.

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형식Review Paper
게재일2024년 05월 (BRIC 등록일 2024-07-04)
연구진국외 연구진
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