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.

Orofacial pain (OFP) is a dental specialty that includes the diagnosis, management and treatment of disorders of the jaw, mouth, face, head and neck. Evidence-based understanding is critical in effectively treating OFPs as the pathophysiology of these conditions is multifactorial. Since OFP impacts the quality of life of the affected individuals, treating patients successfully is of the utmost significance. Despite the therapeutic choices available, treating OFP is still quite challenging, owing to inter-patient variations. The emerging trends in precision medicine could probably lead us to a paradigm shift in effectively managing the untreatable long-standing pain conditions. Precision medicine is designed based on the patient’s genetic profile to meet their needs. Several significant relationships have been discovered based on the genetics and genomics of pain in the past, and some of the notable targets are discussed in this review. The scope of this review is to discuss preclinical and clinical trials that include approaches used in targeted therapy for orofacial pain. Future developments in pain medicine should benefit from current trends in research into novel therapeutic approaches.

Trigeminal neuralgia is unilateral, lancinating, episodic pain that can be provoked by routine activities. Anticonvulsants, such as carbamazepine, are the drugs of choice; however, these possess side-effects. Microvascular decompression is the most effective surgical technique with a higher success rate, although occasionally causes adverse effects. The potential treatment for this type of pain remains unmet. Increased tetrahydrobiopterin (BH4) levels have been reported in association with axonal injury. This study aimed to evaluate the effect of tranilast on relieving neuropathic pain in animal models and analyze the changes in BH4 synthesis. Neuropathic pain was induced via infraorbital nerve constriction. Tranilast, carbamazepine, or saline was injected intraperitoneally to assess the rat’s post-intervention pain response. In the von Frey’s test, the tranilast and carbamazepine groups showed significant changes in the head withdrawal threshold in the ipsilateral whisker pad area. The motor coordination test showed no changes in the tranilast group, whereas the carbamazepine group showed decreased performance, indicating impaired motor coordination. Trigeminal ganglion tissues were used for the PCR array analysis of genes that regulate the BH4 pathway. Downregulation of the sepiapterin reductase (Spr) and aldoketo reductase (Akr) genes after tranilast injection was observed compared to the pain model. These findings suggest that tranilast effectively treats neuropathic pain.

Experimental animal models of orofacial pain have been instrumental in elucidating biological pathways underlying the antinociceptive effect of botulinum neurotoxin type A (BoNT/A). Although several mechanisms have been proposed to explain how BoNT/A relieves pain, the precise modes of action, particularly in the oral and maxillofacial areas, remain elusive. The purpose of this review was to synthesize and assess the latest proposed mechanisms of action through which BoNT/A attenuates orofacial pain in established animal models. A comprehensive search was conducted using the terms “botulinum neurotoxin,” “mechanism,” and “orofacial pain” or “trigeminal neuralgia.” Only animal studies involving the establishment of an orofacial pain model were selected. Additional relevant studies were identified through manual screening of cited references. Over the past five years, several animal pain models have been established to decipher the mechanisms underlying the BoNT/A-mediated antinociception in orofacial pain. The proposed mechanisms include retrograde transport, neuronal excitability regulation, neuropeptide inhibition, inflammatory modulation, and opioid system stimulation in both the peripheral and central nervous systems. Despite the insubstantial number of investigations and findings, BoNT/A exhibits multidimensional modulation of nociceptive responses and, therefore, remains a promising therapeutic agent for managing orofacial pain conditions, with animal studies consistently providing insights into the mechanism of its antinociceptive action.

(1) Background: Chronic psychosocial stress can lead to oral dysesthesia with tongue pain. We examined whether psychosocial stress causes orofacial pain, and analyzed the comprehensive gene expression patterns of circulating cells and transient receptor potential ankyrin 1 (TRPA1) expression in trigeminal ganglion (TG) neurons in a mouse model of psychosocial stress. (2) Methods: Mice were divided into two groups: one group was kept in confrontational housing, and the other group was kept in single housing. Blood, adrenal gland, and tongue were collected. The head withdrawal threshold (HWT) of mechanical stimulation to the whisker pad skin was measured. TRPA1-positive TG neurons were immunohistochemically examined. DNA microarray analysis and quantitative reverse transcription polymerase chain reaction analysis were performed. (3) Results: The HWT was significantly lower in mice under the psychosocial stress condition compared to non-stressed mice. In stress-loaded mice, the number of TRPA1-positive TG neurons was significantly increased. Moreover, we showed that trace amine-associated receptor 7f expression was upregulated in circulating cells in blood and downregulated in the tongue. (4) Conclusions: Our results indicated that chronic psychosocial stress induced the orofacial mechanical allodynia through enhancement of TRPA1 expression in TG neurons with changes in the levels of trace amine-associated receptor 7f.