Targeted Therapy for Orofacial Pain: A Novel Perspective for Precision Medicine
Abstract
:1. Introduction
2. History of Precision Medicine
3. The Need for Advancement of Precision Medicine in Pain Management
4. Precision Medicine Targeting Orofacial Pain
4.1. Voltage-Gated Sodium Channel
4.2. Voltage-Gated Potassium Channel
4.3. Voltage-Gated Calcium Channel
4.4. Transient Receptor Potential Channels
4.5. Serotonin-Gated Ion Channels
4.6. Single Nucleotide Polymorphisms
- Solute carrier family 17 member 9 (SLC17A9) and purinergic receptor P2Y12 (P2RY12) have been reported to be associated with neuropathic pain. Further studies are needed for understanding the detailed mechanisms of pain signal transduction in humans [32].
- Catechol-O-methyltransferase [COMT] is a metabolic enzyme found primarily in postsynaptic neurons and glial cells. Previous reports have shown the participation of COMT in the regulation of neurotransmitters such as dopamine, noradrenaline and adrenaline related to pain [33,34,35,36]. The literature shows evidence of the association of COMT with pain modulation in temporomandibular disorders, which would aid in progressing toward precision medicine.
4.7. Sepiapterin Reductase/GTP Cyclohydrolase 1
4.8. Opioid Receptors
5. Challenges
6. Multifaced Perspectives
6.1. Health Systems
6.2. Nutrition
6.3. Epigenetics
6.4. Genetics
7. Future Directions
8. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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1. | Orofacial pain attributed to disorders of dentoalveolar and anatomically related structures
|
2. | Myofascial orofacial pain
|
3. | Temporomandibular joint (TMJ) pain
|
4. | Orofacial pain attributed to lesion or disease of the cranial nerves
|
5. | Orofacial pains resembling presentations of primary headaches
|
6. | Idiopathic orofacial pain
|
7. | Psychosocial assessment of patients with orofacial pain |
Potential Targets | First Author, Year, Country | Animal and Experiment Condition | Results/Outcome | Opinion |
---|---|---|---|---|
VGSC | Eriksson et al., 2005, Sweden [41] | Rat—Partial ischemic injury to the infraorbital branch of the trigeminal nerve. | The beta 3 subunit was significantly upregulated, whereas the mRNAs for Nav1.8 and Nav 1.9 were reduced in terms of number of neurons and intensities. | Designing a sodium channel subtype-specific blocker from these observations would be helpful for orofacial neuropathic pain therapeutics. |
Luiz et al., 2015, UK [42] | Nav1.9–/– and Nav1.9+/+ mice—Unilateral constriction of the infraorbital nerve. | Reported the role of Nav1.9 sodium channel in the development of thermal and mechanical hypersensitivity. | Regulation of Nav1.9 channel should be investigated for the treatment of orofacial neuropathic pain. | |
VGKC | Madrid at al., 2009, Spain [43] | Neonatal (P1–P6) and adult OF1 mice. | Excitation and inhibition of Kv1 channels modulate the thermosensitive channels. | Suggests the possibility of Kv1 channels in alleviating peripheral gating of cold-evoked discomfort and pain. |
Kanda et al., 2021, AL, USA [44] | Rat—Infraorbital nerve constriction injury (chronic model). | Dysfunction of Kv4.3 channels in sensory neurons of trigeminal ganglion exhibit cold hypersensitivity in orofacial regions leading to neuropathic pain. | Selective Kv4.3 activators may be clinically useful to alleviate trigeminal neuropathic pain. | |
VGCC | Montera et al., 2021, NM, USA [45] | Mice—Foramen rotundum inflammatory Constriction of trigeminal infraorbital nerve. | Upregulation of Cav3.3 in injury model and Cav3.3 blocking significantly reduced allodynia and attenuated neuropathic pain. | Blocking Cav3.3 function may be effective in the treatment of trigeminal neuropathic pain. The blocking of Cav3.3 may be more effective in females. |
Gambeta et al., 2022, Canada [46] | Mice—Constriction of infraorbital nerve. | Antihyperalgesia was the outcome. With the use of a selective T-type calcium channel blocker (Z944). It had no impact in CaV3.2−/− mice. | T-type calcium channel (CaV3.2) is a potential target in trigeminal pain. | |
TRP channels | DeMartini et al., 2018, Italy [47] | Rat—Chronic constriction injury of the infraorbital nerve | TRPA1 and TRPV1 expression levels were markedly increased post injury. | TRPA1 and TRPV1 channels are potential targets in trigeminal neuropathic pain. |
Santos et al., 2022, Brazil [48] | Mice and rat Formalin injection—Temporomandibular joint. Mustard oil injection—Masseter muscle. Chronic model—Infraorbital nerve transection | Findings showed inhibition of orofacial nociception via TRP channels (TRPV1, TRPM3, TRPM8) in both acute and chronic pain models. | Further studies are needed to check whether the same is effective in females as well. Additionally, TRPV2 and TRPV3 could also be involved. | |
Serotonin-gated ion channel | Cornelison et al., 2022, MO, USA [49] | Rat—Inflammation induced by injection of Freund’s adjuvant into the trapezius muscle. | Injection of antagonists of the 5-HT3/7 reduced the symptoms. | Explore the role of 5-HT3 in inhibition of trigeminal nociception. |
SNP | Katagiri et al., 2012, Japan [50] | Rat—Lingual nerve crush. | Demonstrated evidence that activation of P2Y12R following lingual nerve injury induces neuropathic pain. | Satellite glial cells and trigeminal ganglion neuron interactions are involved in the neuron excitability of lingual nerve crush. |
SPR | Raman et al., 2022, Japan [38] | Rat—Infraorbital nerve constriction. | Reported SPR as a novel therapeutic target to treat neuropathic pain | A novel and safe target for new drug designing. |
Opioid receptor MOR DOR | Nunez et al., 2007, MD, USA [51] | Rat—Inflammation induced by injection of Freund’s adjuvant into the masseter muscle. | Increased mRNA and protein expression of MOR 3 days post inflammation. | Contributions of MOR in acute and inflammatory muscle pain conditions. |
Erfanparast et al., 2018, Iran [52] | Rat—Inflammation induced by injection of formalin into the vibrissa pad. | Showed the occurrence of biphasic pain post injection. | Involvement of MOR in modulation of antinociception in orofacial region. | |
Saloman et al., PA, USA [53] | Rat—Orofacial muscle pain condition induced by capsaicin injection. | Pretreatment with DOR agonist attenuated mechanical hypersensitivity. | Role of DOR in mediation of anti-hyperalgesic response in an acute orofacial muscle pain condition. |
Potential Targets | First Author, Year, Country | Patient Population | Results/Outcome | Opinion |
---|---|---|---|---|
VGSC | Siqueira et al., 2009, Brazil [54] | Trigeminal neuralgia at maxillary and/or mandibular branches. n = 10 | Upregulation of Nav1.3 and downregulation of Nav1.7 | The selective expression of particular VGSCs (Nav1.3, Nav1.7, Nav1.8) are suggestive of new targets for drug discovery. |
Zakrzewska et al., 2017, UK [55] | Trigeminal neuralgia patients (based on International Classification of Headache Disorders) (multicenter study) n = 29 | The safety and efficacy of Nav1.7 in patients with trigeminal neuralgia was assessed. Headache was the most common reported adverse effect. | Needs further clinical trials for effective establishment of Nav 1.7 in patients with trigeminal neuralgia. | |
Kotecha et al., 2020, FL, USA [56] | Classical, purely paroxysmal trigeminal neuralgia patients n = 88 | A new design for evaluating VGSCs (vixotrigine) for trigeminal neuralgia patients. | Evaluate the pharmacokinetics of sodium channel blocker for an effective treatment. | |
VGKC | Al-Karagholi et al., 2019, 2020, Denmark [57,58,59] | Migraine patients (1–5 attacks per month) n = 16 | The findings from these trials show evidence of migraine attacks in the opening of ATP-sensitive potassium channels. | The role of ATP-sensitive potassium channels and calcium-activated potassium channels (BKCa) in headaches and migraines and the need for a novel drug is evident. |
Serotonin-gated ion channel | Christidis et al., 2014, Sweden [60] | Temporomandibular disorder patients n = 5 | Increased expression of NaV1.8 by 5-HT3A positive nerve fibers. | 5-HT3 receptor is a biomarker of myofascial temporomandibular disorders. |
SNP | Soeda et al., 2022, Japan [32] | Orofacial pain patients including phantom tooth pain n = 33 | The association of SLC17A9 and P2RY12 with the development of phantom tooth pain was evident. | Larger sample size clinical trials would witness the association of these SNPs in phantom tooth pain. |
Slade et al., 2021, NC, USA [61] | Temporomandibular disorder patients with SNP of COMT gene n = 143 | COMT alters analgesic efficacy. | It could serve as a precision medicine in treating temporomandibular disorders. | |
Opioid receptor MOR | Kleinert et al., 2008, Germany [62] | Patients with post-surgical pain after mandibular third molar extraction n = 400 | Reported the use of tapentadol, a novel, centrally acting analgesic with two modes of action, combining mu-opioid agonism and norepinephrine. Effectively reduced pain. | Single oral dose with limited side effect. |
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Raman, S.; Ikutame, D.; Okura, K.; Matsuka, Y. Targeted Therapy for Orofacial Pain: A Novel Perspective for Precision Medicine. J. Pers. Med. 2023, 13, 565. https://doi.org/10.3390/jpm13030565
Raman S, Ikutame D, Okura K, Matsuka Y. Targeted Therapy for Orofacial Pain: A Novel Perspective for Precision Medicine. Journal of Personalized Medicine. 2023; 13(3):565. https://doi.org/10.3390/jpm13030565
Chicago/Turabian StyleRaman, Swarnalakshmi, Daisuke Ikutame, Kazuo Okura, and Yoshizo Matsuka. 2023. "Targeted Therapy for Orofacial Pain: A Novel Perspective for Precision Medicine" Journal of Personalized Medicine 13, no. 3: 565. https://doi.org/10.3390/jpm13030565