Chemotherapy-related trigeminal and glossopharyngeal nerves neurotoxicity: a cohort study.

BACKGROUND AND OBJECTIVES: The association between orofacial neurotoxicity and chemotherapy treatment is still unclear. In this context, the purpose of this study is to relate the orofacial alterations that manifest during antineoplastic pharmacological treatment, highlighting the drugs commonly related to orofacial neuropathy and the adequate instrument to verify the alterations at clinical levels. METHODS: This prospective cohort study, addressed patients who would start therapy with taxanes, platinum, or related therapy. The collection of signs and symptoms was divided into 3 different times (baseline, second or third cycle of antineoplastic chemotherapy treatment, and sixth cycle). A total of 40 patients were submitted to the application of the Short McGill pain questionnaire and Neutoxicity Induced by Antineoplastics questionnaire (QNIA). To verify sensory alterations in the face, a clinical evaluation was performed with the help of Semmes-Weinstein monofilaments. RESULTS: Taxanes show greater orofacial neurotoxic potential, being associated with sensory alterations assessed by monofilaments (P = .003) and the presence of orofacial pain analyzed by the Short McGill pain questionnaire (P = .001). These medications related to neuropathy in the orofacial region measured through the QNIA, demonstrating a predominantly acute nature (P < .001). CONCLUSION: It is suggested that chemotherapy may induce neurotoxicity in the orofacial region.

[Systematic review and Meta-analysis of efficacy and safety of Bidouyan Oral Liquid in treatment of rhinosinusitis].

This study aimed to systematically review the efficacy and safety of Bidouyan Oral Liquid in the treatment of rhinosinu-sitis(RS). CNKI, Wanfang, SinoMed, VIP, Cochrane Library, PubMed, EMbase, Web of Science, and Ovid were searched for the randomized controlled trial(RCT) of Bidouyan Oral Liquid for the treatment of RS patients. Moreover, the reference lists and the grey literature were searched manually. Two researchers independently screened the literature and extracted data. The Cochrane collaboration's tool for assessing risk of bias(RoB 2.0) in randomized trial was used to assess the methodological quality of the included stu-dies. Meta-analysis was performed in RevMan 5.3 and Stata 12.0, and the grades of recommendation, assessment, development and evaluation(GRADE) was employed to evaluate the quality of evidence. A total of 54 RCTs(35 with drug combinations and 19 with single drugs) comprising 7 511 patients(3 973 in the observation group and 3 538 in the control group) were included. Meta-analysis showed that Bidouyan Oral Liquid + conventional treatment was superior to conventional treatment alone in increasing the total response rate(RR=1.19, 95%CI[1.15, 1.24], P<0.000 01) and decreasing the Lund-Kennedy scores(MD=-1.94, 95%CI[-2.61,-1.26], P<0.000 01), Lund-Mackay scores(MD=-2.14, 95%CI[-2.98,-1.31], P<0.000 01), and visual analogue scale(VAS) scores(MD_(total VAS scores)=-1.28, 95%CI[-1.56,-1.01], P<0.000 01; MD_(nasal congestion VAS scores)=-0.58, 95%CI[-0.89,-0.27], P=0.000 2; MD_(runny nose VAS scores)=-0.61, 95%CI[-0.93,-0.29], P=0.000 2; MD_(olfactory dysfunction VAS scores)=-0.43, 95%CI[-0.52,-0.34], P<0.000 01; MD_(head and facial pain VAS scores)=-0.41, 95%CI[-0.57,-0.26], P<0.000 01). Furthermore, the combined treatment outperformed conventional treatment alone in improving the mucociliary transport rate(MTR)(MD=1.64, 95%CI[1.08, 2.20], P<0.000 01) and lowering the levels of inflammatory cytokines{tumor necrosis factor-α(TNF-α)(SMD=-1.95, 95%CI[-2.57,-1.33], P<0.000 01), interleukin-6(IL-6)(SMD=-2.64, 95%CI[-4.08,-1.21], P=0.000 3)} in RS patients. In addition, the combined treatment did not increase the incidence of adverse reactions(RR=0.83, 95%CI[0.44, 1.57], P=0.57). Bidouyan Oral Liquid was superior to conventional treatment in increasing total response rate(RR=1.25, 95%CI[1.18, 1.32], P<0.000 01), decreasing the Lund-Kennedy(P<0.01) and Lund-Mackay scores(P<0.05), alleviating major symptoms(P_(total VAS scores)<0.01; P_(nasal congestion VAS scores)<0.01; P_(runny nose VAS scores)<0.01; P_(olfactory dysfunction VAS scores)<0.05; P_(head and facial pain VAS scores)<0.01), and decreasing adverse reactions(P=0.03). The results showed that either Bidouyan Oral Liquid or Bidouyan Oral Liquid + conventional treatment can increase the total response rate, decrease the Lund-Kennedy and Lund-Mackay scores, and mitigate major symptoms. In addition, Bidouyan Oral Liquid + conventional treatment improved MTR and reduced the expression of TNF-α and IL-6 without causing serious adverse events. However, due to the limited methodological quality of the included studies, large-sample and high-quality RCTs are needed to provide evidence support.

Non-invasive evaluation of vascular permeability in formalin-induced orofacial pain model using infrared thermography.

Enhanced vascular permeability at the site of injury is a prominent feature in acute inflammatory pain models, commonly assessed through the Evans Blue test. However, this invasive test requires euthanasia, thereby precluding further investigations on the same animal. Due to these limitations, the integration of non-invasive tools such as IRT has been sought. Here, we aimed to evaluate the use of thermography in a common orofacial pain model that employs formalin as a chemical irritant to induce local orofacial inflammation. Male Hannover rats (290-300 g, N = 43) were used. In the first approach, radiometric images were taken before and after formalin administration, assessing temperature changes and extravasated Evans Blue. The second approach included capturing pre- and post-formalin test radiometric images, followed by cytokine measurements in excised vibrissae tissue. Rats were anesthetized for vibrissae tissue collection, allowing correlations between thermographic patterns, nocifensive behavior duration, and cytokine levels in this area. Our findings revealed a positive correlation between local temperature, measured via thermography, and vascular permeability in the contralateral (r2 = 0.3483) and ipsilateral (r2 = 0.4502) side, measured using spectrophotometry. The obtained data supports the notion that thermography-based temperature assessment can effectively evaluate vascular permeability in the orofacial region.

Ketamine for atypical facial pain and hormonal dysregulation: a case report.

BACKGROUND: Ketamine has garnered increased interest for its promising applications in chronic pain treatment, particularly in cases where conventional therapies have proven insufficient. Nevertheless, despite its potential advantages, ketamine remains classified as a third-line medication for pain management. While there are well-documented reactions to ketamine such as hypertension and tachycardia, not much is known about its relationship to cortisol. In this case report, we explicate the administration of ketamine in a patient presenting with atypical facial pain, examining its multifaceted effects on cortisol levels and concurrent pain management. CASE PRESENTATION: A patient with a history of Cushing's disease underwent multiple resections of a pituitary tumor. Afterwards, the patient began experiencing a burning-like pain on the left side of the face. The discomfort was initially treated with a variety of neuromodulatory and anti-inflammatory medications, which caused intolerable side effects and were not effective for pain. As a final recourse, we initiated a regimen of oral compounded ketamine at 5-10 mg three times daily as needed. The patient exhibited marked amelioration in their pain symptoms; however, there was an elevation in their baseline cortisol. In view of the potential risk of inducing Cushing's syndrome, the administration of daily ketamine was discontinued. CONCLUSION: While ketamine is primarily known to control pain through the antagonization of N-methyl-D-aspartate receptors, its effects on cortisol may also contribute to its analgesic properties. Physicians should be aware of the potential for these interactions, particularly when treating patients with a predisposition to hormonal imbalances.

Identification and validation of Rab11a in Rat orofacial inflammatory pain model induced by CFA.

Orofacial pain (OFP) is a clinically very common and the most troubling condition; however, there is few effective way to relieve OFP. Rab11a, a small molecule guanosine triphosphate enzyme, is one of the Rab member family playing a vital role in intracellular endocytosis and the pain process. Therefore, we investigated the hub genes of rat OFP model induced by Complete Freund's Adjuvant (CFA) via re-analyzing microarray data (GSE111160). We found that Rab11a acted as a key hub gene in the process of OFP. During the validation of Rab11a, the OFP model was established by peripheral injection of CFA, which decreased the head withdrawal threshold (HWT) and head withdrawal lantency (HWL). Rab11a was observed in NeuN of Sp5C instead of GFAP/IBA-1, and double-IF of Rab11a and Fos positive cells were increased on the 7th day after CFA modeling statistically. Rab11a protein expression in TG and Sp5C of CFA group was also significantly increased. Interestingly, injection of Rab11a-targeted short hairpin RNA (Rab11a-shRNA) into Sp5C could reverse the decrease in HWT and HWL and reduce the expression level of Rab11a. Electrophysiological recording further demonstrated that the activity of Sp5C neuron was improved in CFA group, while Rab11a-shRNA considerably decreased the enhancement of Sp5C neuronal activity. Finally, we detected the expression level of p-PI3K, p-AKT, and p-mTOR in Sp5C of rats after injecting the Rab11a-shRNA virus. To our surprise, CFA upregulated the phosphorylation of PI3K, AKT and mTOR in Sp5C, and Rab11a-shRNA downregulated these molecules' expression. Our data suggest that CFA activates the PI3K/AKT signaling pathway through up-regulating Rab11a expression, which can induce OFP hyperalgesia development furtherly. Targeting Rab11a may be a novel treatment strategy for OFP.

Association between medication-induced xerostomia and orofacial pain: a systematic review.

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.

Repeated gentle handling or maternal deprivation during the neonatal stage increases adult male rats' baseline orofacial pain responsiveness.

OBJECTIVE: Early life experiences have been found to have a long-lasting effect on brain development in adult life. The purpose of this study was to determine whether neonatal manipulation could alter orofacial pain responsiveness in adult rats METHODS: In the first 21 days of life, male rats were exposed to gentle handling or maternal deprivation (MD) procedures to establish models of handled and MD rats, respectively. The rats were assigned to three of the following experimental groups at the age of two months: intra-dental capsaicin (100 µg), intra-lip formalin (50 µL), and repeated nitroglycerin (NTG) (5 mg/rat/ip) infusion. In addition, there were three drug vehicle groups and three groups that received capsaicin, formalin, or NTG without prior handling or MD procedures. The behaviors were recorded following the pain induction. RESULTS: Spontaneous pain behaviors in the first phase of formalin test was significantly increased in MD (p < 0.01) and handled rats in comparison with the vehicle group (p < 0.05). The second-phase data showed that formalin-induced spontaneous pain behaviors was increased in rats- treated with MD as compared to either vehicle or handled+formalin groups (p < 0.001). Capsaicin-induced dental pulp nociception was increased in the MD group in comparison with the capsaicin (p < 0.001) and capsaicin+handled (p < 0.001) groups. Moreover, NTG-induced migraine-like behaviors symptoms were increased in the MD group as compared to control and handled groups (p < 0.05). CONCLUSIONS: In this study neonatal gentle handling or MD treatment increased orofacial pain in adulthood, showing early life experiences permanent effects on the development of trigeminal circuits in the brain.

Efficacy and mechanism of the antinociceptive effects of cannabidiol on acute orofacial nociception induced by Complete Freund's Adjuvant in male Mus musculus mice.

OBJECTIVES: The objectives were to investigate the efficacy and mechanisms of cannabidiol on orofacial nociception induced by Complete Freund's Adjuvant (CFA) in male Mus musculus mice. DESIGN: For the study of efficacy, mice were divided into seven groups: sham; inflammation; and cannabidiol 0.5, 1, 3, 5, and 10 mg. For the study of mechanisms of cannabidiol, mice were divided into six groups: sham, inflammation, calcitonin gene-related peptide (CGRP) antagonist with and without cannabidiol, and vanilloid receptor 1 antagonist with and without cannabidiol. Spontaneous pain-like behaviors, trigeminal nociception, and trigeminal modulating activity were investigated. RESULTS: CFA injected in the right masseter muscle significantly induced spontaneous pain-like behaviors and the trigeminal nociceptive pathway. This effect was inhibited by injection of 1, 3, 5, and 10 mg of cannabidiol. The 50 % inhibitory concentration of cannabidiol on antinociception was found to be 3 mg/kg. In addition, there was no difference in spontaneous pain-like behaviors with vanilloid receptor 1 antagonist injected before treatment with cannabidiol compared to saline control. Reduced c-fos expression was observed in the trigeminal nucleus caudalis and periaqueductal gray in the group injected with CGRP antagonist before treatment with cannabidiol. CONCLUSION: The antinociceptive effects of cannabidiol induced by acute orofacial nociception is mediated by vanilloid receptor 1 but not by CGRP. Cannabidiol can act with peripheral nonpeptidergic neurons and can be used as an alternative drug or as a synergistic medication in pain treatment.

Orofacial antinociceptive effects of perillyl alcohol associated with codeine and its possible modes of action.

This study evaluated the orofacial antinociceptive effect of (S)-(-)-perillyl alcohol (PA) associated with codeine (C) and investigated the possible molecular anchorage mechanisms of PA. Mice (n = 5 per group) were treated with PA alone and associated with codeine and assigned to the following groups: 75.0 mg/kg PA; 75.0 mg/kg PA + C 30 mg/kg; PA 37.5 mg/kg + C 15.0 mg/kg; C 30.0 mg/kg; and control. Nociception was induced by formalin, capsaicin, and glutamate, and was quantified based on the duration (in seconds) of face grooming. The possible mechanisms of action were evaluated by molecular docking study. In the formalin test, PA75/C30 presented an effect in the neurogenic (p < 0.0001) and inflammatory (p < 0.005) phases. Mice treated with PA75 (p < 0.0001) and PA75/C30 (p < 0.0005) showed a reduced nociceptive behavior in the capsaicin test. Glutamate-induced nociception also was blocked by PA75 (p < 0.0005) and C30 (p < 0.0005). The molecular anchorage analysis indicated high negative binding energy values for the evaluated receptors, especially glutamate receptors (AMPA -79.57 Kcal/mol, mGLUR6 -71.25, and NMDA -66.33 Kcal/mol). PA associated with codeine showed orofacial antinociceptive activity, with theoretical evidence of interaction with glutamate receptors.

Antinociceptive effects of bupivacaine and its sulfobutylether-ß-cyclodextrin inclusion complex in orofacial pain.

Bupivacaine hydrochloride (BVC) represents an option to produce long-lasting analgesia, and complexation in cyclodextrins has shown improvements in biopharmaceutical properties. This study aimed to characterize and test the cytotoxicity and antinociceptive effects of BVC complexed in sulfobutylether-ß-cyclodextrin (SBEßCD). The kinetics and stoichiometry of complexation and BVC-SBEßCD association constant were evaluated by phase solubility study and Job's plot. Evidence of the BVC-SBEßCD complex formation was obtained from scanning electron microscopy (SEM), infrared spectroscopy (FTIR), and differential scanning calorimetry (DSC). The cytotoxicity was evaluated in keratinocyte (HaCaT) and neuroblastoma (SH-SY5Y). Antinociceptive effects were registered via orofacial pain models: the formalin test, carrageenan-induced hyperalgesia, and postoperative pain (intraoral incision). The complex formation occurred at a 1:1 BVC-SBEßCD molar ratio, with a low association constant (13.2 M-1). SEM, DSC, and FTIR results demonstrated the host-guest interaction. The IC50% values determined in SH-SY5Y were 216 µM and 149 µM for BVC and BVC-SBEßCD, respectively (p < 0.05). There was no difference in HaCaT IC50%. In orofacial pain model, BVC-SBEßCD significantly prolonged antinociceptive effect, in about 2 h, compared to plain BVC. SBEßCD can be used as a drug delivery system for bupivacaine, whereas the complex showed long-lasting analgesic effects.

Prolactin signaling modulates stress-induced behavioral responses in a preclinical mouse model of migraine.

OBJECTIVE: The aim of this study was to determine if prolactin signaling modulates stress-induced behavioral responses in a preclinical migraine model. BACKGROUND: Migraine is one of the most complex and prevalent disorders. The involvement of sex-selective hormones in migraine pathology is highly likely as migraine is more common in women and its frequency correlates with reproductive stages. Prolactin has been shown to be a worsening factor for migraine. Normally prolactin levels are low; however levels can surge during stress. Dopamine receptor agonists, which suppress pituitary prolactin release, are an effective migraine treatment in a subset of patients. Previously, we showed that administration of prolactin onto the dura mater induces female-specific behavioral responses, suggesting that prolactin may play a sex-specific role in migraine. METHODS: The effects of prolactin signaling were assessed using a preclinical migraine model we published recently in which behavioral sensitization is induced by repeated stress. Plasma prolactin levels were assessed in naïve and stressed CD-1 mice (n = 3-5/group) and transgenic mice with conditional deletion of the Prlr in Nav1.8-positive sensory neurons (Prlr conditional knock-out [CKO]; n = 3/group). To assess the contribution of prolactin release during stress, naïve or stressed male and female CD-1 mice were treated with the prolactin release inhibitor bromocriptine (2 mg/kg; n = 7-12/group) or vehicle for 5 days (8-12/group) and tested for facial hypersensitivity following stress. Additionally, the contribution of ovarian hormones in regulating the prolactin-induced responses was assessed in ovariectomized female CD-1 mice (n = 6-10/group). Furthermore, the contribution of Prlr activation on Nav1.8-positive sensory neurons was assessed. Naïve or stressed male and female Prlr CKO mice and their control littermates were tested for facial hypersensitivity (n = 8-9/group). Immunohistochemistry was used to confirm loss of Prlr in Nav1.8-positive neurons in Prlr CKO mice. The total sample size is n = 245; the full analysis sample size is n = 221. RESULTS: Stress significantly increased prolactin levels in vehicle-treated female mice (39.70 ± 2.77; p < 0.0001). Bromocriptine significantly reduced serum prolactin levels in stressed female mice compared to vehicle-treated mice (-44.85 ± 3.1; p < 0.0001). Additionally, no difference was detected between female stressed mice that received bromocriptine compared to naïve mice treated with bromocriptine (-0.70 ± 2.9; p = 0.995). Stress also significantly increased serum prolactin levels in male mice, although to a much smaller extent than in females (0.61 ± 0.08; p < 0.001). Bromocriptine significantly reduced serum prolactin levels in stressed males compared to those treated with vehicle (-0.49 ± 0.08; p = 0.002). Furthermore, bromocriptine attenuated stress-induced behavioral responses in female mice compared to those treated with vehicle (maximum effect observed on day 4 post stress [0.21 ± 0.08; p = 0.03]). Bromocriptine did not attenuate stress-induced behavior in males at any timepoint compared to those treated with vehicle. Moreover, loss of ovarian hormones did not affect the ability of bromocriptine to attenuate stress responses compared to vehicle-treated ovariectomy mice that were stressed (maximum effect observed on day 4 post stress [0.29 ± 0.078; p = 0.013]). Similar to CD-1 mice, stress increased serum prolactin levels in both Prlr CKO female mice (27.74 ± 9.96; p = 0.047) and control littermates (28.68 ± 9.9; p = 0.041) compared to their naïve counterparts. There was no significant increase in serum prolactin levels detected in male Prlr CKO mice or control littermates. Finally, conditional deletion of Prlr from Nav1.8-positive sensory neurons led to a female-specific attenuation of stress-induced behavioral responses (maximum effect observed on day 7 post stress [0.32 ± 0.08; p = 0.007]) compared to control littermates. CONCLUSION: These data demonstrate that prolactin plays a female-specific role in stress-induced behavioral responses in this preclinical migraine model through activation of Prlr on sensory neurons. They also support a role for prolactin in migraine mechanisms in females and suggest that modulation of prolactin signaling may be an effective therapeutic strategy in some cases.

NOP01, a NOP receptor agonist, produced potent and peripherally restricted antinociception in a formalin-induced mouse orofacial pain model.

Orofacial pain is one of the most common medical challenges. A preliminary report indicates that the NOP receptor may act as a therapeutic target in orofacial pain. Previous studies have shown that [(pF)Phe4, Aib7, Aib11, Arg14, Lys15]N/OFQ-NH2 (NOP01) functions as a potent NOP receptor peptide agonist. This work aims to investigate the antinociception of NOP01 and its possible action mechanisms in a formalin-induced mouse orofacial pain model at different levels. Our results demonstrated that local, intraperitoneal (i.p.) or intrathecal (i.t.) injection of NOP01 produced dose-related antinociception in both phases of the formalin pain, which could be inhibited by the NOP receptor antagonist but not the classical opioid receptor antagonist. Furthermore, the antinociception induced by systemic NOP01 was blocked by local but not spinal pretreatment with the NOP receptor antagonist, suggesting the involvement of the peripheral NOP receptor in NOP01-induced systemic antinociception. Moreover, local injection of NOP01 markedly suppressed the expression of c-Fos protein induced by formalin in ipsilateral trigeminal ganglion (TG) neurons. In conclusion, this work suggests that NOP01 exerts significant antinociception on orofacial pain at both peripheral and spinal levels via the NOP receptor. Notably, NOP01 cannot readily penetrate the blood-brain barrier. Thus, NOP01 may behave as a potential compound for developing peripherally restricted analgesics.

Modulation of excitatory synaptic transmissions by TRPV1 in the spinal trigeminal subnucleus caudalis neurons of neuropathic pain rats.

The present study examined contribution of the transient receptor potential vanilloid 1 channel (TRPV1) to the chronic orofacial pain. Bilateral partial nerve ligation (PNL) of the mental nerve, a branch of trigeminal nerve, was performed to induce neuropathic pain. The withdrawal threshold in response to mechanical stimulation of the lower lip skin was substantially reduced after the surgery in the PNL rats while it remained unchanged in the sham rats. This reduction in the PNL rats was alleviated by pregabalin injected intraperitoneally (10 mg/kg) and intracisternally (10, 30, 100 µg). Furthermore, an intracisternal injection of AMG9810, an antagonist of TRPV1, (1.5, 5.0 µg) attenuated the reduction of withdrawal threshold. Spontaneous and miniature excitatory postsynaptic currents (sEPSCs and mEPSCs) were recorded from the spinal trigeminal subnucleus caudalis (Vc) neurons in the brainstem slice, which receive the orofacial nociceptive signals. In the PNL rats, superfusion of capsaicin (0.03, 0.1 µM) enhanced their frequency without effect on the amplitude and the highest concentration (0.3 µM) increased both the frequency and amplitude. In the sham rats, only 0.3 µM capsaicin increased their frequency. Thus, capsaicin-induced facilitation of sEPSCs and mEPSCs in the PNL rats was significantly stronger than that in the sham rats. AMG9810 (0.1 µM) attenuated the capsaicin's effect. Capsaicin was ineffective on the trigeminal tract-evoked EPSCs in the PNL and sham rats. These results suggest that the chronic orofacial pain in the PNL model results from facilitation of the spontaneous excitatory synaptic transmission in the Vc region through TRPV1 at least partly.

Association of Hormonal Contraceptive Use with Headache and Temporomandibular Pain: The OPPERA Study.

AIMS: To determine the relationship between hormonal contraceptive (HC) use and painful symptoms, particularly those associated with headache and painful temporomandibular disorders (TMD). METHODS: Data from the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) prospective cohort study were used. During the 2.5-year median follow-up period, quarterly health update (QHU) questionnaires were completed by 1,475 women aged 18 to 44 years who did not have TMD, menopause, hysterectomy, or hormone replacement therapy use at baseline. QHU questionnaires evaluated HC use, symptoms of headache and TMD, and pain of ≥ 1 day duration in 12 body regions. Participants who developed TMD symptoms were examined to classify clinical TMD. Headache symptoms were classified based on the International Classification of Headache Disorders 3 (ICHD-3). Associations between HC use and pain symptoms were analyzed using generalized estimating equations and Cox models. RESULTS: HC use, endorsed in 33.7% of QHU questionnaires, was significantly associated with concurrent symptoms of TMD (odds ratio [OR]: 1.20, 95% CI: 1.06 to 1.35) and headache (OR: 1.26, 95% CI: 1.11 to 1.43). HC use was also significantly associated with concurrent pain of ≥ 1 day duration in the head (OR: 1.38, 95% CI: 1.16 to 1.63), face (OR: 1.44, 95% CI: 1.13 to 1.83), and legs (OR: 1.22, 95% CI: 1.01 to 1.47), but not elsewhere. Initiation of HC use was associated with increased odds of subsequent TMD symptoms (OR: 1.37, 95% CI: 1.13 to 1.66) and pain of ≥ 1 day in the head (OR: 1.37, 95% CI: 1.01 to 1.85). Discontinuing HC use was associated with lower odds of subsequent headache (OR: 0.82, 95% CI: 0.67 to 0.99). HC use was not significantly associated with subsequent onset of examiner-classified TMD. CONCLUSION: These findings imply that HC influences craniofacial pain, and that this pain diminishes after cessation of HC use.

Neurotransmitter and tryptophan metabolite concentration changes in the complete Freund's adjuvant model of orofacial pain.

BACKGROUND: The neurochemical background of the evolution of headache disorders, still remains partially undiscovered. Accordingly, our aim was to further explore the neurochemical profile of Complete Freund's adjuvant (CFA)-induced orofacial pain, involving finding the shift point regarding small molecule neurotransmitter concentrations changes vs. that of the previously characterized headache-related neuropeptides. The investigated neurotransmitters consisted of glutamate, γ-aminobutyric acid, noradrenalin and serotonin. Furthermore, in light of its influence on glutamatergic neurotransmission, we measured the level of kynurenic acid (KYNA) and its precursors in the kynurenine (KYN) pathway (KP) of tryptophan metabolism. METHODS: The effect of CFA was evaluated in male Sprague Dawley rats. Animals were injected with CFA (1 mg/ml, 50 µl/animal) into the right whisker pad. We applied high-performance liquid chromatography to determine the concentrations of the above-mentioned compounds from the trigeminal nucleus caudalis (TNC) and somatosensory cortex (ssCX) of rats. Furthermore, we measured some of these metabolites from the cerebrospinal fluid and plasma as well. Afterwards, we carried out permutation t-tests as post hoc analysis for pairwise comparison. RESULTS: Our results demonstrated that 24 h after CFA treatment, the level of glutamate, KYNA and that of its precursor, KYN was still elevated in the TNC, all diminishing by 48 h. In the ssCX, significant concentration increases of KYNA and serotonin were found. CONCLUSION: This is the first study assessing neurotransmitter changes in the TNC and ssCX following CFA treatment, confirming the dominant role of glutamate in early pain processing and a compensatory elevation of KYNA with anti-glutamatergic properties. Furthermore, the current findings draw attention to the limited time interval where medications can target the glutamatergic pathways.

Involvement of Orexinergic System Within the Nucleus Accumbens in Pain Modulatory Role of the Lateral Hypothalamus in Orofacial Pain Model.

Lateral hypothalamus (LH) contains a large population of orexinergic neurons. Many studies have investigated the function of these neurons and it is clear that they are involved in pain modulation. The nucleus accumbens (NAc) receives many orexinergic projections, and accumbal neurons express both receptors of orexin (OX1R and OX2R). In this study, we investigated the role of accumbal orexinergic receptors in the LH-induced antinociception during formalin-induced orofacial pain. Male adult Wistar rats weighing 230-250 g were used in this study. Cannulae were unilaterally implanted in their skull for microinjections. SB334867 (OX1 receptor antagonist) or TCS OX2 29 (OX2 receptor antagonist) at the doses of 3, 10 and 30 nM were injected into the NAc with/without intra-LH microinjection of carbachol (250 nM/rat). Carbachol was used for chemical stimulation of orexinergic neurons in the LH. Our results showed that intra-LH carbachol following injection of formalin into animals' upper lip reduced nociception in both phases of formalin test. SB334867 and TCS OX2 29 were able to reduce LH-induced antinociception in both phases. Although the highest dose of SB334867 and TCS OX2 29 (30 nM) was effective in both phases, the TCS OX2 29 but not SB334867 at the dose of 10 nM could not reduce the antinociceptive responses induced by LH stimulation during the first (early) phase. It suggests that contribution of accumbal orexinergic receptors in the first phase of formalin test is more than the second (late) phase, and these results provide further evidence for the involvement of orexinergic system in the modulation of inflammatory orofacial pain.

Activation of the RAS/B-RAF-MEK-ERK pathway in satellite glial cells contributes to substance p-mediated orofacial pain.

The cross talk between trigeminal ganglion (TG) neurons and satellite glial cells (SGCs) is crucial for the regulation of inflammatory orofacial pain. Substance P (SP) plays an important role by activating neurokinin (NK)-I receptors in this cross talk. The activation of extracellular signal-regulated kinase (ERK) 1/2, protein kinase A (PKA) and protein kinase C (PKC) in neurons and SGCs of peripheral ganglions by peripheral inflammation is associated with inflammatory hypersensitivity. This study tested the hypothesis that SP evoked SP-NK-I receptor positive feedback via the Renin-Angiotensin System/B-Protein Kinase A-Rapidly Accelerates Fibrosarcoma-MEK-Extracellular Signal-Regulated Kinase (RAS/PKA-RAF-MEK-ERK) pathway, which is involved in pain hypersensitivity. Inflammatory models were induced in vivo by injecting Complete Freund's adjuvant (CFA) into the whisker pad of rats. SP was administrated to SGCs in vitro for investigating, whether SP regulates the expression of NK-I receptor in the SGC nucleus. The effects of RAS-RAF-MEK, PKA and PKC pathways in this process were measured by co-incubating SGCs with respective Raf, PKA, PKC and MEK inhibitors in vitro and by pre-injecting these inhibitors into the TG in vivo. SP significantly upregulated NK-I receptor, p-ERK1/2, Ras, B-Raf, PKA and PKC in SGCs under inflammatory conditions. In addition, L703,606 (NK-I receptor antagonist), U0126 (MEK inhibitor), Sorafenib (Raf inhibitor) and H892HCL (PKA inhibitor) but not chelerythrine chloride (PKC inhibitor) significantly decreased NK-I mRNA and protein levels induced by SP. The allodynia-related behavior evoked by CFA was inhibited by pre-injection of L703,606, U0126, Sorafenib and H892HCL into the TG. Overall, SP upregulates NK-I receptor in TG SGCs via PKA/RAS-RAF-MEK-ERK pathway activation, contributing to a positive feedback of SP-NK-I receptor in inflammatory orofacial pain.

The P2Y14 receptor in the trigeminal ganglion contributes to the maintenance of inflammatory pain.

P2Y purinergic receptors expressed in neurons and satellite glial cells (SGCs) of the trigeminal ganglion (TG) contribute to inflammatory and neuropathic pain. P2Y14 receptor expression is reported in the spinal cord, dorsal root ganglion (DRG), and TG. In present study, the role of P2Y14 receptor in the TG in inflammatory orofacial pain of Sprague-Dawley (SD) rats was investigated. Peripheral injection of complete Freund's adjuvant (CFA) induced mechanical hyperalgesia with the rapid upregulation of P2Y14 receptor, glial fibrillary acidic protein (GFAP), interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α), C-C chemokine CCL2, phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2), and phosphorylated p38 (p-p38) proteins in the TG. Furthermore, immunofluorescence staining confirmed the CFA-induced upregulation of P2Y14 receptor. Double immunostaining showed that P2Y14 receptor colocalized with glutamine synthetase (GS) and neuronal nuclei (NeuN). Finally, trigeminal injection of a selective antagonist (PPTN) of P2Y14 receptor attenuated CFA-induced mechanical hyperalgesia. PPTN also decreased the upregulation of the GFAP, IL-1ß, TNF-α, CCL2, p-ERK1/2, and p-p38 proteins. Our findings showed that P2Y14 receptor in TG may contribute to orofacial inflammatory pain via regulating SGCs activation, releasing cytokines (IL-1ß, TNF-α, and CCL2), and phosphorylating ERK1/2 and p38.

The effect of orofacial complete Freund's adjuvant treatment on the expression of migraine-related molecules.

BACKGROUND: Migraine is a neurovascular primary headache disorder, which causes significant socioeconomic problems worldwide. The pathomechanism of disease is enigmatic, but activation of the trigeminovascular system (TS) appears to be essential during the attack. Migraine research of recent years has focused on neuropeptides, such as calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating polypeptide 1-38 (PACAP1-38) as potential pathogenic factors and possible therapeutic offensives. The goal of present study was to investigate the simultaneous expression of CGRP and precursor of PACAP1-38 (preproPACAP) in the central region of the TS in a time-dependent manner following TS activation in rats. METHODS: The right whisker pad of rats was injected with 50 µl Complete Freund's Adjuvant (CFA) or saline. A mechanical allodynia test was performed with von Frey filaments before and after treatment. Transcardial perfusion of the animals was initiated 24, 48, 72 and 120 h after injection, followed by the dissection of the nucleus trigeminus caudalis (TNC). After preparation, the samples were stored at - 80 °C until further use. The relative optical density of CGRP and preproPACAP was analyzed by Western blot. One-way ANOVA and Kruskal-Wallis followed by Tukey post hoc test were used to evaluate the data. Regression analysis was applied to explore the correlation between neuropeptides expression and hyperalgesia. RESULTS: Orofacial CFA injection resulted in significant CGRP and preproPACAP release in the TNC 24, 48, 72 and 120 h after the treatment. The level of neuropeptides reached its maximum at 72 h after CFA injection, corresponding to the peak of facial allodynia. Negative, linear correlation was detected between the expression level of neuropeptides and value of mechanonociceptive threshold. CONCLUSION: This is the first study which suggests that the expression of CGRP and preproPACAP simultaneously increases in the central region of activated TS and it influences the formation of mechanical hyperalgesia. Our results contribute to a better understanding of migraine pathogenesis and thereby to the development of more effective therapeutic approaches.

Chemotherapy-Induced First Bite Syndrome: A Case Report in a Patient With Hodgkin Lymphoma.

Vinca alkaloids are known to cause bilateral jaw pain that occurs once during the chemotherapy course. We report a patient with first bite syndrome (FBS) during active treatment with chemotherapy. A patient with Hodgkin lymphoma presented with unilateral jaw pain after beginning his chemotherapy regimen. Pain was worse with the first bite of each meal and dissipated over subsequent bites. Workup was negative for any lesions in the parotid, parapharyngeal space, or infratemporal fossa. Pain was timed closely with chemotherapy administration and would improve prior to next cycle. A trial of botulinum chemodenervation failed to completely relieve symptoms. The patient noted resolution of symptoms after the completion of chemotherapy. We report a case of FBS, which may represent the jaw pain seen commonly with administration of vinca alkaloids. There appears to be a correlation between onset and duration of first bite symptoms with chemotherapy administration.