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Transmembrane Cav2.2 (N-type) voltage-gated calcium channels are genetically and pharmacologically validated, clinically relevant pain targets. Clinical block of Cav2.2 (e.g., with Prialt/Ziconotide) or indirect modulation [e.g., with gabapentinoids such as Gabapentin (GBP)] mitigates chronic pain but is encumbered by side effects and abuse liability. The cytosolic auxiliary subunit collapsin response mediator protein 2 (CRMP2) targets Cav2.2 to the sensory neuron membrane and regulates their function via an intrinsically disordered motif. A CRMP2-derived peptide (CBD3) uncouples the Cav2.2-CRMP2 interaction to inhibit calcium influx, transmitter release, and pain. We developed and applied a molecular dynamics approach to identify the A1R2 dipeptide in CBD3 as the anchoring Cav2.2 motif and designed pharmacophore models to screen 27 million compounds on the open-access server ZincPharmer. Of 200 curated hits, 77 compounds were assessed using depolarization-evoked calcium influx in rat dorsal root ganglion neurons. Nine small molecules were tested electrophysiologically, while one (CBD3063) was also evaluated biochemically and behaviorally. CBD3063 uncoupled Cav2.2 from CRMP2, reduced membrane Cav2.2 expression and Ca2+ currents, decreased neurotransmission, reduced fiber photometry-based calcium responses in response to mechanical stimulation, and reversed neuropathic and inflammatory pain across sexes in two different species without changes in sensory, sedative, depressive, and cognitive behaviors. CBD3063 is a selective, first-in-class, CRMP2-based peptidomimetic small molecule, which allosterically regulates Cav2.2 to achieve analgesia and pain relief without negative side effect profiles. In summary, CBD3063 could potentially be a more effective alternative to GBP for pain relief.
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Dolor Crónico , Peptidomiméticos , Ratas , Animales , Dolor Crónico/tratamiento farmacológico , Dolor Crónico/metabolismo , Ratas Sprague-Dawley , Peptidomiméticos/farmacología , Calcio/metabolismo , Canales de Calcio Tipo N/genética , Canales de Calcio Tipo N/metabolismo , Células Receptoras Sensoriales/metabolismo , Ganglios Espinales/metabolismoRESUMEN
BACKGROUND: Genetic variation in the catechol-O-methyltransferase (COMT) gene is associated with sensitivity to both acute experimental pain and chronic pain conditions. Four single nucleotide polymorphisms (SNPs) have traditionally been used to infer three common haplotypes designated as low, average and high pain sensitivity and are reported to affect both COMT enzymatic activity and pain sensitivity. One mechanism that may partly explain individual differences in sensitivity to pain is conditioned pain modulation (CPM). We hypothesized that variation in CPM may have a genetic basis. METHODS: We evaluated CPM in 77 healthy pain-free Caucasian subjects by applying repeated mechanical stimuli to the dominant forearm using 26-g von Frey filament as the test stimulus with immersion of the non-dominant hand in hot water as the conditioning stimulus. We assayed COMT SNP genotypes by the TaqMan method using DNA extracted from saliva. RESULTS: SNP rs4680 (val158 met) was not associated with individual differences in CPM. However, CPM was associated with COMT low pain sensitivity haplotypes under an additive model (p = 0.004) and the effect was independent of gender. CONCLUSIONS: We show that, although four SNPs are used to infer COMT haplotypes, the low pain sensitivity haplotype is determined by SNP rs6269 (located in the 5' regulatory region of COMT), suggesting that inherited variation in gene expression may underlie individual differences in pain modulation. Analysis of 13 global populations revealed that the COMT low pain sensitivity haplotype varies in frequency from 13% to 44% and showed that two SNPs are sufficient to distinguish all COMT haplotypes in most populations.
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Catecol O-Metiltransferasa/genética , Individualidad , Dolor/genética , Polimorfismo de Nucleótido Simple , Adulto , Anciano , Anciano de 80 o más Años , Análisis Mutacional de ADN/métodos , Femenino , Estudios de Asociación Genética , Genotipo , Haplotipos , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , Dimensión del Dolor/métodos , Umbral del Dolor/fisiología , Adulto JovenRESUMEN
BACKGROUND: Pain may undergo modulation in the central nervous system prior to reaching the primary somatosensory cortex and being perceived as pain. Faulty pain modulation mechanisms have been linked to various chronic pain conditions. Cytokines such as IL-10 and IL-1beta, are known to be involved in initiation and maintenance of neuropathic pain. In this study, we investigated the association between pain modulation profile, pain intensity and cytokines (IL-10 and IL-1beta) levels in a rat model of neuropathic pain. METHODS: Exercise-Induced Hypoalgesia (EIH) was assessed by evaluating the percentage of responses to a train of 60g mechanical stimuli before and after 180 seconds of exercise on a rotating rod. The differences in the response rates before and after the exercise were used to divide the rats into low and high EIH responders. Rats from low and high EIH groups underwent constriction injury of the left sciatic nerve. Pain behavior (allodynia and hyperalgesia) were assessed by measuring responses to mechanical and thermal stimuli applied to the plantar surface of the foot. Serum, sciatic nerve and the related Dorsal Root Ganglia (DRG) levels of IL-10 and IL-1beta were determined by ELISA. The DRG mRNA levels of IL-10 and IL-1beta measured with PCR. A comparison between the low and high EIH rats of all measured parameters was made. RESULTS: The low EIH rats developed significantly more severe allodynia and hyperalgesia in the affected paw and allodynia in the contralateral paw compared to the high EIH rats, 7 days following the injury. The low EIH rats had higher IL-1beta protein levels in serum prior to and following injury, higher affected and contralateral sciatic nerve IL-1beta levels following injury and higher IL-1beta levels in the contralateral DRG (protein and mRNA) following injury when compared to high EIH rats. The high EIH rats had higher affected sciatic nerve IL-10 levels following nerve injury and higher IL-10 levels of both protein and mRNA in the affected and contralateral DRG at baseline and following injury. CONCLUSION: EIH profile was found to be predictive of pain behavior following nerve injury, low EIH rats developed more severe allodynia and hyperalgesia. IL-1beta may be associated with painful neuropathy developed in rats with low EIH while the anti-inflammatory cytokine IL-10 may have a protective role, inhibiting the development of painful.
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Interleucina-10/sangre , Interleucina-1beta/sangre , Tejido Nervioso/lesiones , Dolor/sangre , Dolor/patología , Condicionamiento Físico Animal , Animales , Hiperalgesia/sangre , Hiperalgesia/complicaciones , Masculino , Tejido Nervioso/patología , Dolor/complicaciones , Dimensión del Dolor , Ratas Sprague-Dawley , Índice de Severidad de la EnfermedadRESUMEN
Melanocortin-4 receptor (MC4R) has been investigated as a potential drug target for the treatment of neuropathic pain. The objective of the study was to systematically identify the effects of MC4R antagonists on hypersensitivity in rat models of neuropathic pain. A systematic search was conducted using the following databases: WoS, PubMed, SCOPUS, and MEDLINE. Inclusion criteria were: rat hypersensitivity induced by models of neuropathic pain with reported effects of MC4R antagonist. Two researchers performed the selection process and data extraction. SYRCLE risk of bias tool was used. Standard mean differences (SMD) were calculated and pooled by meta-analysis using random effect models. Ten articles met the eligibility criteria and were included in the systematic review and meta-analysis. The results reveal that, in animals exposed to neuropathic pain, administration of MC4R antagonists significantly increased paw withdrawal threshold (SHU9119 SMD = 1.67, 95% CI: [0.91, 2.44], I2 = 0%; HS014 SMD = 2.2, 95% CI: [0.53, 3.87], I2 = 71%) and heat withdrawal latency (HS014 SMD = 3.35, 95% CI: [0.56, 6.14], I2 = 83%) compared to vehicle-treated animals. MC4R antagonists are effective in the alleviation of hypersensitivity in rodent neuropathic pain models. SHU9119 and HS014 antagonists showed the most prominent results. However, further investigation is needed to determine the optimal dose and time of treatment.
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Neuralgia , Receptor de Melanocortina Tipo 4 , Animales , Modelos Animales de Enfermedad , Hiperalgesia , Neuralgia/tratamiento farmacológico , RatasRESUMEN
Painful traumatic trigeminal neuropathy (PTTN) may occur following major craniofacial or oral trauma, or may be subsequent to relatively minor dental interventions. Following injury, pain may originate from a peripheral nerve, a ganglion, or from the central nervous system. In this review, we focus on molecular mechanisms of pain resulting from injury to the peripheral branch of the trigeminal nerve. This syndrome has been termed painful traumatic trigeminal neuropathy (PTTN) by the International Headache Society and replaces previous terms including atypical odontalgia, deafferentation pain, traumatic neuropathy and phantom toothache. We emphasize the scientific evidence supporting the events purported to lead to PTTN by reviewing the pathophysiology of PTTN based on relevant animal models. Additionally, we briefly overview clinical correlates and pathophysiological manifestations of PTTN.
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Experimentación Animal , Enfermedades del Nervio Trigémino , Traumatismos del Nervio Trigémino , Animales , Dolor , Dimensión del Dolor , Enfermedades del Nervio Trigémino/genética , Enfermedades del Nervio Trigémino/fisiopatologíaRESUMEN
Painful traumatic trigeminal neuropathy (PTTN) is a chronic neuropathic pain that may develop following injury to the trigeminal nerve. Etiologies include cranio-orofacial trauma that may result from dental, surgical, or anesthetic procedures or physical trauma, such as a motor vehicle accident. Following nerve injury, there are various mechanisms, including peripheral and central, as well as phenotypic changes and genetic predispositions that may contribute to the development of neuropathic pain. In this article, we review current literature pertaining to the cellular processes that occur following traumatic damage to the trigeminal nerve, also called cranial nerve V, that results in chronic neuropathic pain. We examine the neurobiology and pathophysiology based mostly on pre-clinical animal models of neuropathic/trigeminal pain.
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Mechanisms underlying neuropathic pain (NP) are complex with multiple genes, their interactions, environmental and epigenetic factors being implicated. Transcriptional changes in the trigeminal (TG) and dorsal root (DRG) ganglia have been implicated in the development and maintenance of NP. Despite efforts to unravel molecular mechanisms of NP, many remain unknown. Also, most of the studies focused on the spinal system. Although the spinal and trigeminal systems share some of the molecular mechanisms, differences exist. We used RNA-sequencing technology to identify differentially expressed genes (DEGs) in the TG and DRG at baseline and 3 time points following the infraorbital or sciatic nerve injuries, respectively. Pathway analysis and comparison analysis were performed to identify differentially expressed pathways. Additionally, upstream regulator effects were investigated in the two systems. DEG (differentially expressed genes) analyses identified 3,225 genes to be differentially expressed between TG and DRG in naïve animals, 1,828 genes 4 days post injury, 5,644 at day 8 and 9,777 DEGs at 21 days postinjury. A comparison of top enriched canonical pathways revealed that a number of signaling pathway was significantly inhibited in the TG and activated in the DRG at 21 days postinjury. Finally, CORT upstream regulator was predicted to be inhibited in the TG while expression levels of the CSF1 upstream regulator were significantly elevated in the DRG at 21 days postinjury. This study provides a basis for further in-depth studies investigating transcriptional changes, pathways, and upstream regulation in TG and DRG in rats exposed to peripheral nerve injuries. PERSPECTIVE: Although trigeminal and dorsal root ganglia are homologs of each other, they respond differently to nerve injury and therefore treatment. Activation/inhibition of number of biological pathways appear to be ganglion/system specific suggesting that different approaches might be required to successfully treat neuropathies induced by injuries in spinal and trigeminal systems.
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Neuralgia , Traumatismos de los Nervios Periféricos , Ratas , Animales , Ganglios Espinales/metabolismo , Transcriptoma , Ganglio del Trigémino/metabolismo , Traumatismos de los Nervios Periféricos/genética , Traumatismos de los Nervios Periféricos/metabolismo , Neuralgia/genética , Neuralgia/metabolismoRESUMEN
Background: Despite recent advances in our knowledge of genetic contributions to the highly variable sickle cell disease (SCD) phenotype, our understanding of genetic factors associated with pain sensitivity in SCD remains limited. Previous studies investigated specific variants in single candidate genes and their association with SCD pain variability. The primary aim of the current study was to expand the genes and polymorphisms tested to discover new risk genes (polymorphisms) associated with central sensitization for individuals with SCD. Methods: Adults with sickle cell disease (n = 59, Mage = 36.8 ± 11.5, 65.8 % female) underwent quantitative sensory testing to examine central sensitization and general pain sensitivity. Participants reported average crisis and non-crisis pain intensities weekly using a 0-100 scale, and provided salivary samples for genotyping. The Hardy-Weinberg equilibrium was verified for controls, and allele distributions were tested with chi-square and odds ratio tests. The Benjamini-Hochberg procedure was used to control for false discovery rate. Regression analyses and Wilcoxon tests were used to test associations for normally distributed and skewed data, respectively. Results: Central sensitization and general pain sensitivity were not associated with hemoglobin genotype (Ps > 0.05). Of 4145 SNPs tested, following false discovery rate adjustments, 11 SNPs (rs11575839, rs12185625, rs12289836, rs1493383, rs2233976, rs3131787, rs3739693, rs4292454, rs4364, rs4678, rs6773307) were significantly associated with central sensitization, and one SNP (rs7778077) was significantly associated with average weekly non-crisis pain. No SNPs were associated with general pain sensitivity. Conclusions: These findings provide insights into genetic variants association with average non-crisis pain and central sensitization for individuals with SCD, and may provide support for genetic predictors of heightened pain experience within SCD.
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ABSTRACT: Dysregulation of voltage-gated sodium Na V 1.7 channels in sensory neurons contributes to chronic pain conditions, including trigeminal neuropathic pain. We previously reported that chronic pain results in part from increased SUMOylation of collapsin response mediator protein 2 (CRMP2), leading to an increased CRMP2/Na V 1.7 interaction and increased functional activity of Na V 1.7. Targeting this feed-forward regulation, we developed compound 194 , which inhibits CRMP2 SUMOylation mediated by the SUMO-conjugating enzyme Ubc9. We further demonstrated that 194 effectively reduces the functional activity of Na V 1.7 channels in dorsal root ganglia neurons and alleviated inflammatory and neuropathic pain. Here, we used a comprehensive array of approaches, encompassing biochemical, pharmacological, genetic, electrophysiological, and behavioral analyses, to assess the functional implications of Na V 1.7 regulation by CRMP2 in trigeminal ganglia (TG) neurons. We confirmed the expression of Scn9a , Dpysl2 , and UBE2I within TG neurons. Furthermore, we found an interaction between CRMP2 and Na V 1.7, with CRMP2 being SUMOylated in these sensory ganglia. Disrupting CRMP2 SUMOylation with compound 194 uncoupled the CRMP2/Na V 1.7 interaction, impeded Na V 1.7 diffusion on the plasma membrane, and subsequently diminished Na V 1.7 activity. Compound 194 also led to a reduction in TG neuron excitability. Finally, when intranasally administered to rats with chronic constriction injury of the infraorbital nerve, 194 significantly decreased nociceptive behaviors. Collectively, our findings underscore the critical role of CRMP2 in regulating Na V 1.7 within TG neurons, emphasizing the importance of this indirect modulation in trigeminal neuropathic pain.
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Dolor Crónico , Péptidos y Proteínas de Señalización Intercelular , Proteínas del Tejido Nervioso , Neuralgia del Trigémino , Enzimas Ubiquitina-Conjugadoras , Animales , Ratas , Dolor Crónico/tratamiento farmacológico , Dolor Crónico/metabolismo , Ganglios Espinales , Ratas Sprague-Dawley , Células Receptoras Sensoriales/metabolismo , Neuralgia del Trigémino/tratamiento farmacológico , Neuralgia del Trigémino/metabolismo , Enzimas Ubiquitina-Conjugadoras/antagonistas & inhibidores , Administración Intranasal , Proteínas del Tejido Nervioso/antagonistas & inhibidoresRESUMEN
OBJECTIVE: Xerostomia (or oral dryness) is most commonly caused by medications that affect saliva secretion, and is often accompanied by symptoms of orofacial pain. Medication-induced xerostomia may or may not be associated with objectively demonstrable hyposalivation. The present study attempted to systematically identify an association between medication-induced xerostomia and orofacial pain. METHOD AND MATERIALS: A systematic search was conducted using the following databases: WoS, PubMed, SCOPUS, and MEDLINE. The search terms used were: xerostomia OR "dry mouth" AND medication AND ("oral pain" OR "orofacial pain" OR "craniofacial pain" OR "burning mouth" OR "glossodynia") NOT Sjögren's NOT cancer. Inclusion criteria were medication-induced xerostomia and reported symptoms of orofacial pain. Four researchers performed the selection process and quality assessment and two researchers conducted data extraction. RESULTS: Seven studies with a total of 1,029 patients were included. These studies were conducted between 2009 and 2022 and consisted of cross-sectional studies, case-control studies, and one randomized crossover trial. The studies consisted of a total of 1,029 participants. All studies included male and female participants whose mean ages ranged from 43 to 100 years. CONCLUSIONS: A positive association was found between medication-induced xerostomia and orofacial pain. No associations were found between salivary flow measurements (hyposalivation) and medication use. Future research should focus on saliva flow measurements, standardized assessment of medication-induced xerostomia, as well as the inclusion of accompanying orofacial pain diagnosis in the medical history to allow for higher level of evidence in establishing reliable predictors of medication-induced oral health damage to facilitate clinical prevention and management.
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Xerostomía , Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Estudios Transversales , Xerostomía/inducido químicamente , Saliva , Dolor Facial/inducido químicamente , Estudios de Casos y Controles , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
BACKGROUND: Exercise is a known trigger of the inhibitory pain modulation system and its analgesic effect is termed exercise-induced hypoalgesia (EIH). Previous studies have demonstrated that rats with deficient analgesic response following exercise develop more significant hypersensitivity following nerve injury compared to rats with substantial analgesic response following exercise. OBJECTIVES: A rat model of EIH as an indicator of the pain inhibitory system's efficiency was used to explore the association between EIH profiles and the effect of pharmacotherapy on rat's neuropathic pain. METHODS: EIH profiles were assessed by evaluating paw responses to mechanical stimuli before and after exercise on a rotating rod. Rats with a reduction of ≤33% in responses were classified as low EIH and those with ≥67% as high EIH. Low and high EIH rats underwent sciatic nerve chronic constriction injury (CCI). Paw responses to mechanical stimuli were measured at baseline, following CCI, and after treatment with diclofenac, duloxetine or pregabalin. In a different group of low and high EIH rats, EIH was measured before and following treatment with the same medications. RESULTS: Low EIH rats developed more significant hypersensitivity following CCI. Duloxetine and pregabalin successfully reduced hypersensitivity, although significantly more so in low EIH rats. Diclofenac had limited effects, and only on low EIH rats. Four days of duloxetine administration transformed low EIH rats' profiles to high EIH. CONCLUSIONS: The findings of this study suggest that EIH profiles in rats can not only predict the development of hypersensitivity following injury but may also support targeted pharmacological treatment. SIGNIFICANCE: Exercise is a known trigger of the inhibitory pain modulation. Rats with deficient analgesic response following exercise develop more significant hypersensitivity following nerve injury. Pain modulation profiles in rats can also support targeted pharmacological treatment; rats with deficient analgesic response following exercise benefit more from treatment with duloxetine and gabapentin. Treatment with duloxetine can improve pain modulation profile.
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Neuralgia , Traumatismos de los Nervios Periféricos , Ratas , Animales , Pregabalina/farmacología , Pregabalina/uso terapéutico , Clorhidrato de Duloxetina/farmacología , Clorhidrato de Duloxetina/uso terapéutico , Diclofenaco/efectos adversos , Neuralgia/tratamiento farmacológico , Neuralgia/inducido químicamente , Analgésicos/efectos adversos , Traumatismos de los Nervios Periféricos/complicaciones , Traumatismos de los Nervios Periféricos/tratamiento farmacológico , Constricción Patológica/tratamiento farmacológico , Umbral del Dolor/fisiologíaRESUMEN
Treatment of chronic orofacial pain remains a major therapeutic challenge despite available medications. Melanocortins have been implicated in pathologic pain. Intrathecal administration of MC4R antagonists has been shown to alleviate neuropathic pain (NP) in male rats. However, intrathecal delivery is very invasive and requires surgeon's intervention. Intra-nasal rout offers a non-invasive drug delivery method that can be self-administered making it very attractive clinically. In this study, we investigated the effects of intra-nasally delivered MC4R antagonist (HS014) on trigeminal neuropathic pain (TNP) in male and female rats. We also measured the MC4R protein levels in the trigeminal ganglia (TG) and infraorbital nerve (ION) of rats. We used ION chronic constriction injury (ION-CCI) to induce TNP in rats. We used von Frey and pinprick assays to measure the development of hypersensitivity in the face following ION-CCI. At 22 days post-ION-CCI, we delivered HS014 intra-nasally to measure its effects on TNP in rats. We used enzyme linked immunosorbent assay to measure MC4R protein levels in the TG and ION. ION-CCI resulted in a significant increase of MC4R protein levels in the ipsilateral TG and ION of male and female rats. Intra-nasal delivered HS014 resulted in a significant reduction of ION-CCI induced hypersensitivity in male and female rats. These results demonstrate that intranasal delivery of MC4R antagonist alleviated TNP in male and female rats and suggest that such treatment could be beneficial therapeutically for individuals with chronic NP.
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Neuralgia , Neuralgia del Trigémino , Femenino , Ratas , Masculino , Animales , Hiperalgesia/tratamiento farmacológico , Receptor de Melanocortina Tipo 4 , Neuralgia del Trigémino/tratamiento farmacológico , Neuralgia del Trigémino/metabolismo , Neuralgia/tratamiento farmacológico , Neuralgia/metabolismo , Dolor Facial/tratamiento farmacológicoRESUMEN
Dysregulation of voltage-gated sodium Na V 1.7 channels in sensory neurons contributes to chronic pain conditions, including trigeminal neuropathic pain. We previously reported that chronic pain results in part from increased SUMOylation of collapsin response mediator protein 2 (CRMP2), leading to an increased CRMP2/Na V 1.7 interaction and increased functional activity of Na V 1.7. Targeting this feed-forward regulation, we developed compound 194 , which inhibits CRMP2 SUMOylation mediated by the SUMO-conjugating enzyme Ubc9. We further demonstrated that 194 effectively reduces the functional activity of Na V 1.7 channels in dorsal root ganglia neurons and alleviated inflammatory and neuropathic pain. Here, we employed a comprehensive array of investigative approaches, encompassing biochemical, pharmacological, genetic, electrophysiological, and behavioral analyses, to assess the functional implications of Na V 1.7 regulation by CRMP2 in trigeminal ganglia (TG) neurons. We confirmed the expression of Scn9a , Dpysl2 , and UBE2I within TG neurons. Furthermore, we found an interaction between CRMP2 and Na V 1.7, with CRMP2 being SUMOylated in these sensory ganglia. Disrupting CRMP2 SUMOylation with compound 194 uncoupled the CRMP2/Na V 1.7 interaction, impeded Na V 1.7 diffusion on the plasma membrane, and subsequently diminished Na V 1.7 activity. Compound 194 also led to a reduction in TG neuron excitability. Finally, when intranasally administered to rats with chronic constriction injury of the infraorbital nerve (CCI-ION), 194 significantly decreased nociceptive behaviors. Collectively, our findings underscore the critical role of CRMP2 in regulating Na V 1.7 within TG neurons, emphasizing the importance of this indirect modulation in trigeminal neuropathic pain.
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Trigeminal nerve injury is one of the causes of chronic orofacial pain. Patients suffering from this condition have a significantly reduced quality of life. The currently available management modalities are associated with limited success. This article reviews some of the common causes and clinical features associated with post-traumatic trigeminal neuropathic pain (PTNP). A cascade of events in the peripheral and central nervous system function is involved in the pathophysiology of pain following nerve injuries. Central and peripheral processes occur in tandem and may often be co-dependent. Due to the complexity of central mechanisms, only peripheral events contributing to the pathophysiology have been reviewed in this article. Future investigations will hopefully help gain insight into trigeminal-specific events in the pathophysiology of the development and maintenance of neuropathic pain secondary to nerve injury and enable the development of new therapeutic modalities.
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Neuralgia , Traumatismos del Nervio Trigémino , Neuralgia del Trigémino , Humanos , Calidad de Vida , Neuralgia del Trigémino/complicaciones , Neuralgia del Trigémino/terapia , Neuralgia/etiología , Neuralgia/tratamiento farmacológico , Dolor Facial/complicaciones , Dolor Facial/terapia , Traumatismos del Nervio Trigémino/complicacionesRESUMEN
BACKGROUND/PURPOSE: Burning mouth syndrome (BMS) is a chronic condition presenting as intraoral burning or dysesthesia, with a high preponderance in menopausal women. This study aimed to examine the association between somatosensory dysfunction and BMS in premenopausal, early postmenopausal, and late postmenopausal patients, using a standardized Quantitative Sensory Testing (QST) protocol, and to determine the predictive value of thermal or mechanical perception by QST for detecting BMS. MATERIALS AND METHODS: An observational case-control study was performed with 36 female participants with BMS (12 premenopausal, 10 early postmenopausal, and 14 late postmenopausal) and 42 age- and sex-matched healthy volunteers (21 premenopausal, 10 early postmenopausal, and 11 late postmenopausal). Neurophysiological tests were used to evaluate somatosensory dysfunction at the tongue. RESULTS: Z-score in the late postmenopausal BMS group revealed a gain of function for the cold pain threshold and heat pain threshold (Z = 2.08 and 3.38, respectively). In the multiple regression analysis with the Visual Analog Scale as the dependent variable, the vibration detection threshold predicted the severity of burning mouth sensation in the premenopausal group. CONCLUSION: Late postmenopausal patients with BMS showed an increased response of the tongue to noxious thermal stimuli. This supports the theory that changes in sex hormones may affect trigeminal somatosensory function, particularly during the late postmenopausal stage in patients with BMS.
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BACKGROUND: Nerve injury can lead to ectopic activation of injured nociceptorsand central sensitization characterized by allodynia and hyperalgesia. Reduction in the activity of primary afferent neurons has been shown to be sufficient in alleviating peripherally generated pain. The cell bodies of such trigeminal nociceptors are located in the trigeminal ganglia (TG) with central processes that terminate in the brainstem trigeminal nucleus caudalis (TNC). The TG is therefore a strategic locus where afferent input can be manipulated. We hypothesized that chemogenetic inhibition of TG would suppress TNC neuronal activity and attenuate pain behaviour in a rat model of painful traumatic trigeminal neuropathy (PTTN). METHODS: Trigeminal neuropathic pain was induced in adult male Sprague-Dawley rats (n = 24) via chronic constriction injury to the infraorbital nerve (ION-CCI). Naïve and sham rats were used as controls (n = 20/group). Rats within each group received TG-directed microinjections of AAV virus containing either the inhibitory hM4Di-DREADD construct or EGFP. RESULTS: In the ION-CCI group, systemic administration of the DREADD agonist clozapine N-oxide (CNO) reversed the hypersensitivity phenotype in animals expressing hM4Di but not EGFP. CNO-mediated activation of hM4Di DREADD in ION-CCI animals was also associated with reduced Fos expression in the TNC elicited by repeated mechanical stimulation of the dermatome ipsilateral to the injury. There was no effect of CNO on pain behaviour or TNC Fos expression in eGFP animals. CONCLUSION: Our results indicate that DREADDs may offer an effective therapeutic approach for treatment of trigeminal neuropathic pain. SIGNIFICANCE: Trigeminal neuropathic pain is highly resistant to therapy and we are in dire need of novel approaches. This study provides further evidence for the successful application of DREADDs as an effective tool for modulating central nervous system function. CNO mediated activation of hM4Di-DREADDs in the trigeminal ganglion (TG) attenuates nerve injury induced neuropathic pain by acting on hyperactive TG cells. It also establishes the TG as an effective target to manage pain in the face and head. Accessing the TG in clinical populations is a relatively simple and safe procedure, making this approach highly significant. Moreover, the methodology described here has applications in trigeminal neuropathic pain from traumatic other etiologies and in spinal neuropathic pain. Chronic pain syndromes are characterized by a progressive failure of brain centers to adequately inhibit pain and as these are identified, we may be able to target them for therapy. Therefore, our findings might have wide application in chronic pain syndromes.
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Neuralgia , Neuralgia del Trigémino , Animales , Hiperalgesia , Masculino , Neuralgia/tratamiento farmacológico , Neuronas/metabolismo , Ratas , Ratas Sprague-Dawley , Ganglio del Trigémino/metabolismo , Neuralgia del Trigémino/tratamiento farmacológicoRESUMEN
AIMS: To investigate the role of exercise-induced hypoalgesia (EIH) in the development of neuropathic pain (NP) following infraorbital nerve (ION) injury and to explore possible underlying mechanisms defining the differences between rats with high and low EIH. METHODS: EIH was evaluated by measuring the percentage of withdrawal responses to a series of 30 mechanical stimuli applied to the hind paw before and after 180 seconds of exercise on a rotating rod. The rats were assigned to low- and high-EIH groups based on reduction in the percent of withdrawal responses following exercise. NP was induced in high- and low-EIH rats via ION constriction injury. Rats were tested with graded nylon monofilaments to establish the withdrawal threshold. Increasingly stiff monofilaments were applied to the ION territory until there was a clear withdrawal by the rat. This was repeated a total of three times. A decreased withdrawal threshold indicates allodynia. Testing was performed at baseline and at 3, 10, and 17 days following the injury. On day 17 postinjury, IONs were harvested for the assessment of interleukin (IL)-6, IL-1ß, and IL-10 levels. Samples from high-EIH and low-EIH surgically naïve rats served as control for the cytokines study. In this second part of the study, the effects of cannabinoid 1 (CB1) and cannabinoid 2 (CB2) antagonists and naltrexone on EIH profiles and on the withdrawal thresholds to mechanical stimulation were measured. EIH and withdrawal thresholds in high- and low-EIH rats were measured before and after administration of antagonists. RESULTS: Low-EIH rats developed significantly more pronounced allodynia in the ION territory following injury compared to high-EIH rats. At 17 days postinjury, ION IL-1ß levels were higher in low-EIH rats, and IL-10 levels were higher in high-EIH rats. CB1 antagonist blocked the analgesic effect induced by exercise in high- but not in low-EIH rats. The CB2 antagonist had no significant effect on high- or low-EIH rats. Naltrexone blocked the effects of EIH in both high- and low-EIH rats. Exercise induced a significant analgesic effect in high-EIH but not in low-EIH rats. CB1 or CB2 antagonist administration had no effect on pre-exercise responses to mechanical stimulation, while naltrexone administration resulted in significant allodynia in both low- and high-EIH rats. CONCLUSION: This study demonstrated substantial differences between rats with high and low EIH. The results suggest that following ION injury, high-EIH rats may have a more prominent or activated endocannabinoids system and that their inflammatory response is moderated, with higher levels of IL-10 and lower levels of IL-1ß.
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Endocannabinoides , Neuralgia , Analgésicos Opioides , Animales , Citocinas , Endocannabinoides/farmacología , Hiperalgesia , Umbral del Dolor , RatasRESUMEN
OBJECTIVES: Endodontic treatment is a routine procedure performed by general dental practitioners and endodontists on a daily basis. Fortunately, most patients undergoing endodontic therapy show a favorable outcome with uneventful healing. However, some patients develop pain following endodontic therapy. A majority of these patients develop acute, nociceptive pain ("flare-up") that resolves with appropriate treatment and subsequent healing. The dental profession is very adept at successfully managing the acute pain that occurs early following endodontic treatment. A minority of patients, however, develop ongoing pain following root canal therapy, termed chronic if persisting for 3 months or more. The diagnosis and management of chronic postendodontic pain are often challenging. This article aims to review pain following endodontic therapy, ranging from acute to chronic pain and its management, with specific emphasis on chronic pain, its pathophysiology, clinical features, diagnostic criteria, and management modalities. CONCLUSION: Endodontic treatment rarely leads to chronic neuropathic pain; however, when the nerve injury occurs and results in posttraumatic trigeminal neuropathic pain (PTNP), treatment options are very limited and rarely successful. Therefore, all steps should be taken to avoid nerve injury. Prevention of endodontic treatment related PTNP is crucial and achieved through early recognition, and prompt management.
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Dolor Crónico , Odontólogos , Atención Odontológica , Humanos , Rol Profesional , Tratamiento del Conducto Radicular/efectos adversosRESUMEN
AIMS: To assess the speed and accuracy of a checklist user interface for the Diagnostic Criteria for Temporomandibular Disorders (DC/TMD). METHODS: A diagnostic tool formatted as a checklist was developed and compared to an existing diagnostic tool, the DC/TMD diagnsostic decision trees. Both types of tools use the DC/TMD and were tested by dental students, interns, and residents in the USA and Japan for diagnosis of hypothetical patients. The comparisons were done in a randomized, crossover, controlled, double-blinded trial. RESULTS: Overall, subjects using the experimental tool answered 25% more correct diagnoses (P < .001) and missed 27% fewer diagnoses (P < .01). They were also able to finalize their diagnoses faster than those using the control tool, in 16% less time (P < .05). The difference in accuracy was more pronounced in complex cases, while the difference in speed was more pronounced in simple cases. CONCLUSION: This checklist is an alternative user interface for the DC/TMD.
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Trastornos de la Articulación Temporomandibular , Comportamiento del Uso de la Herramienta , Estudios Cruzados , Dolor Facial , Humanos , Trastornos de la Articulación Temporomandibular/diagnósticoRESUMEN
BACKGROUND: The dorsal root (DRG) and trigeminal (TG) ganglia contain cell bodies of sensory neurons of spinal and trigeminal systems, respectively. They are homologs of each other; however, differences in how the two systems respond to injury exist. Trigeminal nerve injuries rarely result in chronic neuropathic pain (NP). To date, no genes involved in the differential response to nerve injury between the two systems have been identified. We examined transcriptional changes involved in the development of trigeminal and spinal NP. METHODS: Trigeminal and spinal mononueropathies were induced by chronic constriction injury to the infraorbital or sciatic nerve. Expression levels of 84 genes in the TG and DRG at 4, 8 and 21 days post-injury were measured using real-time PCR. RESULTS: We found time-dependent and ganglion-specific transcriptional regulation that may contribute to the development of corresponding neuropathies. Among genes significantly regulated in both ganglia Cnr2, Grm5, Htr1a, Il10, Oprd1, Pdyn, Prok2 and Tacr1 were up-regulated in the TG but down-regulated in the DRG at 4 days post-injury; at 21 days post-injury, Adora1, Cd200, Comt, Maob, Mapk3, P2rx4, Ptger1, Tnf and Slc6a2 were significantly up-regulated in the TG but down-regulated in the DRG. CONCLUSIONS: Our findings suggest that spinal and trigeminal neuropathies due to trauma are differentially regulated. Subtle but important differences between the two ganglia may affect NP development. SIGNIFICANCE: We present distinct transcriptional alterations in the TG and DRG that may contribute to differences observed in the corresponding mononeuropathies. Since the trigeminal system seems more resistant to developing NP following trauma our findings lay ground for future research to detect genes and pathways that may act in a protective or facilitatory manner. These may be novel and important therapeutic targets.