Potential Molecular Targets for Treating Neuropathic Orofacial Pain Based on Current Findings in Animal Models

Abstract

This review highlights potential molecular targets for treating neuropathic orofacial pain based on current findings in animal models. Preclinical research is currently elucidating the pathophysiology of the disease and identifying the molecular targets for better therapies using animal models that mimic this category of orofacial pain, especially post-traumatic trigeminal neuropathic pain (PTNP) and primary trigeminal neuralgia (PTN). Animal models of PTNP and PTN simulate their etiologies, that is, trauma to the trigeminal nerve branch and compression of the trigeminal root entry zone, respectively. Investigations in these animal models have suggested that biological processes, including inflammation, enhanced neuropeptide-mediated pain signal transmission, axonal ectopic discharges, and enhancement of interactions between neurons and glial cells in the trigeminal pathway, are underlying orofacial pain phenotypes. The molecules associated with biological processes, whose expressions are substantially altered following trigeminal nerve damage or compression of the trigeminal nerve root, are potentially involved in the generation and/or exacerbation of neuropathic orofacial pain and can be potential molecular targets for the discovery of better therapies. Application of therapeutic candidates, which act on the molecular targets and modulate biological processes, attenuates pain-associated behaviors in animal models. Such therapeutic candidates including calcitonin gene-related peptide receptor antagonists that have a reasonable mechanism for ameliorating neuropathic orofacial pain and meet the requirements for safe administration to humans seem worth to be evaluated in clinical trials. Such prospective translation of the efficacy of therapeutic candidates from animal models to human patients would help develop better therapies for neuropathic orofacial pain.

Interactions Among Non-Coding RNAs and mRNAs in the Trigeminal Ganglion Associated with Neuropathic Pain

“… 1 However, highly effective treatments or drugs for trigeminal neuropathic pain are still unavailable because of the lack of a complete understanding of its mechanisms. 3 , 6 Although increasing data demonstrate that ncRNAs (miRNAs, lncRNAs, and circRNAs) play crucial roles in neuropathic pain, little is known about the expression profile and roles of ncRNAs in the TG under the condition of trigeminal neuropathic pain. As far as we know, this study was the first to study the expression profile of miRNAs, lncRNAs, and circRNAs in the TG of CCI-ION mice (a classical trigeminal neuropathic pain model) by whole-transcriptome sequencing and bioinformatics analysis.…”

“…It often occurs after injuries to the trigeminal sensory fibers induced by trauma and tooth iatrogenic injuries from dental treatments, such as local anesthetic injections, root canal therapies, extractions, oral surgery, dental implants, orthognathic surgery, and other invasive procedures. 1,2 Although lots of potential intervention molecular targets in the trigeminal ganglion (TG) for treating trigeminal neuropathic pain have been found, 3 for instance, multiple groups of molecules (ATP, glutamate, SP, IL-1β, and TNF-α), receptors (P2X, NMDAR, NK1, and GPCRs), ion channels (voltagegated potassium channels and voltage-gated calcium channels), and intracellular signaling pathways (MAPKs, PKC, PKA), [3][4][5] consistently effective treatment options are still not available. 3,6 Therefore, more preclinical research is expected to elucidate the molecular mechanism underlying trigeminal neuropathic pain and identify novel therapeutic targets to develop a more effective treatment for trigeminal neuropathic pain.…”

Pain Relief in a Trigeminal Neuralgia Model via Optogenetic Inhibition on Trigeminal Ganglion Itself With Flexible Optic Fiber Cannula

“…Trigeminal thalamic ventral posteromedial nucleus (VPm) neurons display greater spontaneous activity, wider receptive field size, low activation threshold, and hence heightened excitability following trigeminal nerve injury or inflammation ( Aguilar and Castro-Alamancos, 2005 ). The TG is primarily comprised of pseudounipolar primary afferent neurons and glial cells with cell bodies surrounded by a single layer of SGCs ( Nagakura et al, 2021 ). Neuronal activation occurs, and various molecules are up- or downregulated in the TG in response to trigeminal nerve injury, which is apparent in the peripheral nervous system ( Suzuki et al, 2013 ).…”

Post-traumatic Trigeminal Neuropathic Pain: Factors Affecting Surgical Treatment Outcomes

“…Allodynia is a painful response to a normally nonpainful stimuli, hyperpathia is a complex painful response to repetitive nonpainful stimulus, and hyperalgesia is a lowered pain threshold to a painful stimulus. The cause of PTTNp is still unknown but animal studies have implicated various biological processes such as inflammation, enhanced neuropeptide-mediated pain signal transmission, endothelial receptor activity, and glial cell dysfunction causing trigeminal hyperexcitability [ 10 ]. PTTNp may be diagnosed clinically by clinical neurosensory testing as described by Zuniga and Essick [ 11 ].…”