Ro5-4864, a translocator protein ligand, regulates T cell-mediated inflammatory responses in skin.

Translocator protein (TSPO) is a mitochondrial outer membrane protein expressed on a variety of immune cells, including macrophages, dendritic cells, and T cells, in addition to neurons and steroid-producing cells. Previous studies of TSPO ligands have suggested that TSPO is involved in multiple cellular functions, including steroidogenesis, immunomodulation, and cell proliferation. Currently, there are limited reports on the effects of TSPO or TSPO ligands on T cell-mediated immune responses. We here investigated the involvement of TSPO/TSPO ligand in T cell responses using a 2,4-dinitro-1-fluorobenzene (DNFB)-induced contact hypersensitivity (CH) model. Treatment with Ro5-4864, a TSPO ligand, during DNFB sensitization reduced the number and activation status of CD4+ and CD8+ T cells in draining lymph nodes and alleviated skin inflammation after DNFB challenge. Adoptive transfer of Ro5-4864-treated mouse-derived DNFB-sensitized T cells to naïve mice inhibited CH responses after DNFB challenge. Ro5-4864-treated sensitized T cells showed lower proliferative responses when stimulated with DNFB-pulsed antigen-presenting cells compared to control-treated sensitized T cells. Ro5-4864 also suppressed cell proliferation, as well as adenosine triphosphate and lactate production, during T cell activation. Moreover, the inhibitory effects of Ro5-4864 on T cell responses were conserved in TSPO-deficient cells. Our results suggest that Ro5-4864 inhibits CH responses by suppressing energy metabolism, at least via glycolysis, to reduce the T cell primary response in a TSPO-independent manner.

TMEM132C rs7296262 Single-Nucleotide Polymorphism Is Significantly Associated with Nausea Induced by Opioids Administered for Cancer Pain and Postoperative Pain.

Opioids are almost mandatorily used for analgesia for cancer pain and postoperative pain. Opioid analgesics commonly induce nausea as a side effect. However, the genetic factors involved are still mostly unknown. To clarify the genetic background of individual differences in the occurrence of nausea during opioid administration, the incidence of nausea was investigated in 331 patients (Higashi-Sapporo Hospital [HS] group) who received morphine chronically for cancer pain treatment and in 2021 patients (Cancer Institute Hospital [CIH] group) who underwent elective surgery under general anesthesia. We conducted a genome-wide association study of nausea in HS samples. Among the top 20 candidate single-nucleotide polymorphisms (SNPs), we focused on the TMEM132C rs7296262 SNP, which has been reportedly associated with psychiatric disorders. The rs7296262 SNP was significantly associated with nausea in both the HS and CIH groups (TT+TC vs. CC; HS group, p = 0.0001; CIH group, p = 0.0064). The distribution of nausea-prone genotypes for the rs7296262 SNP was reversed between HS and CIH groups. These results suggest that the TMEM132C rs7296262 SNP is significantly associated with nausea during opioid use, and the effect of the SNP genotype on nausea is reversed between chronic and acute phases of opioid use.

A Case Report on Unstable Angina Pectoris Manifesting as Orofacial Pain.

Cardiac ischemia, such as angina pectoris or myocardial infarction, is associated with pain in the oral cavity, lower jaw, head, or neck, or spanning from the left upper arm to the shoulder. When presenting to a dentist, however, appropriate treatment for such patients is often delayed, as dental problems are usually the first to be suspected when the chief complaint is orofacial pain. This report describes a case of a 70-year-old woman who was aware of pain and a burning sensation in the oral cavity upon exertion for a year prior to presenting at our clinic. She had been examined by her family physician, an otolaryngologist, and another dentist, none of whom found any abnormalities other than suspected periodontal disease and caries, for which she was treated. An examination at our clinic revealed no abnormal dental findings that would have been consistent with the mandibular pain, however. Although no chest symptoms were reported, pain was elicited on exertion, suggesting cardiogenic toothache. An immediate referral to a cardiologist was therefore made on the same day. The patient visited the cardiology department of the University Hospital of Tokyo Dental College 6 days later. The increased frequency of symptoms on exertion suggested unstable angina, and the patient was admitted to the emergency department on the same day. Emergency coronary angiography showed that right coronary artery #1 was 99% stenosed proximally (highly calcified plaque). The diagnosis was unstable angina pectoris, with the right coronary artery #1 as the responsible lesion, and percutaneous coronary angioplasty was performed on the same day. Subsequently, all the orofacial pain disappeared, confirming unstable angina as the cause. The pain characteristics in this case were consistent with pain associated with cardiac ischemia, which led to the immediate referral to the cardiology department. In cases of toothache associated with cardia ischemia, it is essential to seek cardiological care as soon as possible.

The rs216009 single-nucleotide polymorphism of the CACNA1C gene is associated with phantom tooth pain.

Phantom tooth pain (PTP) is a rare and specific neuropathic pain that occurs after pulpectomy and tooth extraction, but its cause is not understood. We hypothesized that there is a genetic contribution to PTP. The present study focused on the CACNA1C gene, which encodes the α1C subunit of the Cav1.2 L-type Ca2+ channel (LTCC) that has been reported to be associated with neuropathic pain in previous studies. We investigated genetic polymorphisms that contribute to PTP. We statistically examined the association between genetic polymorphisms and PTP vulnerability in 33 patients with PTP and 118 patients without PTP but with pain or dysesthesia in the orofacial region. From within and around the CACNA1C gene, 155 polymorphisms were selected and analyzed for associations with clinical data. We found that the rs216009 single-nucleotide polymorphism (SNP) of the CACNA1C gene in the recessive model was significantly associated with the vulnerability to PTP. Homozygote carriers of the minor C allele of rs216009 had a higher rate of PTP. Nociceptive transmission in neuropathic pain has been reported to involve Ca2+ influx from LTCCs, and the rs216009 polymorphism may be involved in CACNA1C expression, which regulates intracellular Ca2+ levels, leading to the vulnerability to PTP. Furthermore, psychological factors may lead to the development of PTP by modulating the descending pain inhibitory system. Altogether, homozygous C-allele carriers of the rs216009 SNP were more likely to be vulnerable to PTP, possibly through the regulation of intracellular Ca2+ levels and affective pain systems, such as those that mediate fear memory recall.

Genetic Polymorphisms of ENPP2 Are Possibly Associated with Pain Severity and Opioid Dose Requirements in Patients with Inflammatory Pain Conditions: Clinical Observation Study.

Autotaxin, encoded by the ENPP2 gene, is a known key element of neuropathic pain; however, its involvement in nociceptive pain processing remains unclear. We explored the associations between postoperative pain intensity, 24-h postoperative opioid dose requirements, and 93 ENNP2-gene single-nucleotide polymorphisms (SNPs) in 362 healthy patients who underwent cosmetic surgery using the dominant, recessive, and genotypic models. Next, we validated the associations between relevant SNPs on the one hand and pain intensity and daily opioid dosages on the other in 89 patients with cancer-related pain. In this validation study, a Bonferroni correction for multiplicity was applied on all relevant SNPs of the ENPP2 gene and their respective models. In the exploratory study, three models of two SNPs (rs7832704 and rs2249015) were significantly associated with postoperative opioid doses, although the postoperative pain intensity was comparable. In the validation study, the three models of the two SNPs were also significantly associated with cancer pain intensity (p < 0.017). Patients with a minor allele homozygosity complained of more severe pain compared with patients with other genotypes when using comparable daily opioid doses. Our findings might suggest that autotaxin is associated with nociceptive pain processing and the regulation of opioid requirements.

Rs11726196 Single-Nucleotide Polymorphism of the Transient Receptor Potential Canonical 3 (TRPC3) Gene Is Associated with Chronic Pain.

Chronic pain is reportedly associated with the transient receptor potential canonical 3 (TRPC3) gene. The present study examined the genetic associations between the single-nucleotide polymorphisms (SNPs) of the TRPC3 gene and chronic pain. The genomic samples from 194 patients underwent linkage disequilibrium (LD) analyses of 29 SNPs within and around the vicinity of the TRPC3 gene. We examined the associations between the SNPs and the susceptibility to chronic pain by comparing the genotype distribution of 194 patients with 282 control subjects. All SNP genotype data were extracted from our previous whole-genome genotyping results. Twenty-nine SNPs were extracted, and a total of four LD blocks with 15 tag SNPs were observed within and around the TRPC3 gene. We further analyzed the associations between these tag SNPs and chronic pain. The rs11726196 SNP genotype distribution of patients was significantly different from the control subjects even after multiple-testing correction with the number of SNPs. The TT + TG genotype of rs11726196 is often carried by chronic pain patients, suggesting a causal role for the T allele. These results contribute to our understanding of the genetic risk factors for chronic pain.

Single-Nucleotide Polymorphisms of the PAR2 and IL-17A Genes Are Significantly Associated with Chronic Pain.

Patients with chronic pain are affected psychologically and socially. There are also individual differences in treatment efficacy. Insufficient research has been conducted on genetic polymorphisms that are related to individual differences in the susceptibility to chronic pain. Autoimmune disorders can lead to inflammation and chronic pain; therefore, we focused on the autoimmune-related protease-activated receptor 2 (PAR2/F2RL1) and interleukin 17A (IL-17A/IL17A) genes. PAR2 and IL-17A are associated with autoimmune diseases that lead to chronic pain, and PAR2 regulates T-helper (Th) cell activation and differentiation. We hypothesized that the PAR2 and IL-17A genes are associated with chronic pain. The present study used a case-control design to statistically examine associations between genetic polymorphisms and the vulnerability to chronic pain. The rs2243057 polymorphism of the PAR2 gene and rs3819025 polymorphism of the IL-17A gene were previously reported to be associated with pain- or autoimmune-related phenotypes. Thus, these polymorphisms were investigated in the present study. We found that both rs2243057 and rs3819025 were significantly associated with a susceptibility to chronic pain. The present findings revealed autoimmune-related genetic factors that are involved in individual differences in chronic pain, further aiding understanding of the pathomechanism that underlies chronic pain and possibly contributing to future personalized medicine.

FGF4 and FGF9 have synergistic effects on odontoblast differentiation.

The purpose of this study was to investigate whether fibroblast growth factor 4 (FGF4) and FGF9 are active in dentin differentiation. Dentin matrix protein 1 (Dmp1) -2A-Cre transgenic mice, which express the Cre-recombinase in Dmp1-expressing cells, were crossed with CAG-tdTomato mice as reporter mouse. The cell proliferation and tdTomato expressions were observed. The mesenchymal cell separated from neonatal molar tooth germ were cultured with or without FGF4, FGF9, and with or without their inhibitors ferulic acid and infigratinib (BGJ398) for 21 days. Their phenotypes were evaluated by cell count, flow cytometry, and real-time PCR. Immunohistochemistry for FGFR1, 2, and 3 expression and the expression of DMP1 were performed. FGF4 treatment of mesenchymal cells obtained promoted the expression of all odontoblast markers. FGF9 failed to enhance dentin sialophosphoprotein (Dspp) expression levels. Runt-related transcription factor 2 (Runx2) was upregulated until day 14 but was downregulated on day 21. Compared to Dmp1-negative cells, Dmp1-positive cells expressed higher levels of all odontoblast markers, except for Runx2. Simultaneous treatment with FGF4 and FGF9 had a synergistic effect on odontoblast differentiation, suggesting that they may play a role in odontoblast maturation.

A Case of Suspected Negative Pressure Pulmonary Edema after General Anesthesia.

Negative pressure pulmonary edema (NPPE) can occur rapidly after the release of an upper airway obstruction. In general anesthesia, NPPE can be caused by laryngospasm after extubation. This report describes a case in which NPPE was thought to have occurred after extubation during general anesthesia in a disabled person. The patient was a 28-yearold man, 160 cm in height and 56 kg in weight, who was scheduled for dental caries treatment under ambulatory general anesthesia due to intellectual disability. After induction of general anesthesia, nasal intubation was performed after sufficient oral suctioning to remove a large amount of serous secretion. After completion of dental treatment, pressurized extubation was performed after oral suctioning as sufficient spontaneous breathing and body movement were observed. Immediately after extubation, SpO2 dropped to 80%, subsequently recovering to 99% under oxygen administration at 5 liter/min with an oxygen mask. It dropped to approximately 85% again, however, when administration of oxygen was discontinued. Although communication with the patient was difficult, no expression of anguish or dyspnea was observed. A chest radiograph showed symmetric middle-lobe and lingular segment infiltrates, and the patient was transferred to the nearest general hospital. No obvious clinical findings other than a decrease in SpO2 were observed, suggesting NPPE as a result of airway narrowing due to secretions.

Effects of changes in end-tidal carbon dioxide tension on oral tissue blood flow and tissue oxygen tension during remifentanil infusion in rabbits.

PURPOSE: The aim of this study was to investigate the effects of end-tidal carbon dioxide tension (ETCO2) changes during remifentanil infusion on mandibular bone marrow tissue blood flow (BBF), masseter muscle tissue blood flow (MBF), mandibular bone marrow tissue oxygen tension (PbO2) and masseter muscle tissue oxygen tension (PmO2) in rabbits. METHODS: Ten male tracheotomized Japan White rabbits were anesthetized and ventilated with sevoflurane. ETCO2 was adjusted to 30 mmHg. After baseline measurement, CO2 was added to the inhaled air, and ETCO2 was increased to 40 and 60 mmHg. Heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), BBF, MBF, PbO2, and PmO2 were recorded with and without remifentanil infusion at 0.4 µg/kg/min. RESULTS: Two-way repeated measures analysis of variance showed no interaction between ETCO2 and remifentanil in all variables. Remifentanil infusion produced decreases in HR, SBP, MAP, BBF and MBF compared with those without remifentanil infusion, while it did not affect DBP, PbO2 and PmO2. Elevation of ETCO2 from 30 to 60 mmHg produced decreases in HR and MBF, and increases in SBP, DBP, MAP and BBF, while it did not affect PbO2 and PmO2. CONCLUSION: PbO2 and PmO2 remained unchanged despite changes in BBF and MBF during ETCO2 change with or without remifentanil infusion.

Neuropathic Pain in Lower Lip after Guided Tissue Regeneration: A Case Report.

Post-traumatic trigeminal neuropathic pain is mainly caused by the extraction of third molars or the placement of dental implants. This report describes the treatment of neuropathic pain arising after guided tissue regeneration (GTR). The patient was a 55-year-old woman who had to undergo GTR due to severe periodontitis in the distal aspect of the right mandibular second molar. Postoperatively, the patient had been prescribed mecobalamin for hypesthesia and allodynia in the right lower lip. No improvement was observed in these symptoms after 4 months, however, so she was referred to our Orofacial Pain Center. Preoperative and postoperative cone-beam computed tomography revealed a cyst-like lesion (radiolucent area) close to the right mandibular second molar and canal. Although the results of quantitative sensory examination were normal, rubbing the right lower lip with a cotton swab elicited mechanical allodynia. The diagnosis was post-traumatic trigeminal neuropathic pain for which the patient was given pregabalin and Neurotropin®. The symptoms improved within approximately 32 weeks, with the medication being terminated at 64 weeks. Although hypoesthesia due to nerve injury may suddenly go into remission, allodynia is often intractable. If symptoms show no improvement after 3 months, possible nerve injury should be investigated. Additionally, the distal root of the mandibular molar may be close to the inferior alveolar nerve, necessitating appropriate diagnostic imaging of the operative field. If the lesion or distal root is close to the inferior alveolar nerve, postoperative hypesthesia or neuropathic pain may occur, even without direct trauma.

Direct Mechanical Stimulation Mediates Cell-to-Cell Interactions in Cultured Trigeminal Ganglion Cells.

Trigeminal neuralgia occurs in the orofacial region, characteristically causing pain that feels like a transient electric shock. Some histopathological studies have reported that trigeminal neuralgia is caused by mechanical compression of the demyelinated trigeminal nerve; the pathophysiological mechanism behind this phenomenon remains to be clarified, however. Cell-cell interactions have also been reported to be involved in the development and modulation of some types of neuropathic pain. The purpose of this study was to investigate the potential contribution of cell-cell interactions to trigeminal neuralgia by measuring intracellular free Ca2+ concentrations ([Ca2+]i) in primary cultured trigeminal ganglion (TG) cells. Direct mechanical stimulation of TG cells induced an increase in [Ca2+]i in both neuronal and non-neuronal cells, such as glial cells. Moreover, this increase was stimulus intensity-dependent and non-desensitizing. Direct mechanical stimulation increased [Ca2+]i in neighboring cells as well, and this increase was inhibited by application of carbamazepine. These results indicate that direct mechanical stimulation affects Ca2+ signaling. Trigeminal ganglion cells establish intercellular networks between themselves, suggesting that this is involved in the development and generation of trigeminal neuralgia.

Effects of KnockOut Serum Replacement on Differentiation of Mouse-Induced Pluripotent Stem Cells into Odontoblasts.

Serum serves as a source of rich nutrients during in vitro cell culture, facilitating cell adhesion, growth, and differentiation. When culturing stem cells for transplantation, however, it must be remembered that such culture medium may contain substances potentially harmful to the proposed recipient and may even induce cellular damage. The purpose of this study was to determine whether KnockOut Serum Replacement (KSR), a chemically defined medium supplement, enhanced in vitro differentiation of induced pluripotent stem cells into odontoblasts. Cranial neural crest cells, precursors of odontoblasts, were generated from mouse-induced pluripotent stem cells. They were then cultured in serum-free Dulbecco's modified Eagle's/F12 medium containing fibroblast growth factor 8 with or without KSR. The cells cultured with KSR showed strong proliferation, acquired a spindle-like morphology, and connected with the surrounding cells. KnockOut Serum Replacement also boosted expression of odontoblast markers as measured by qRT-PCR, and increased dentin sialoprotein as assessed by immunostaining. These results confirmed that mouse-induced pluripotent stem cells differentiated into odontoblasts under serum-free conditions, and that KSR enhanced the efficiency of this process.

Cold pain sensitivity is associated with single-nucleotide polymorphisms of PAR2/F2RL1 and TRPM8.

Pain sensitivity differs individually, but the mechanisms and genetic factors that underlie these differences are not fully understood. To investigate genetic factors that are involved in sensing cold pain, we applied a cold-induced pain test and evaluated protease-activated receptor 2 (PAR2/F2RL1) and transient receptor potential melastatin 8 (TRPM8), which are related to pain. We statistically investigated the associations between genetic polymorphisms and cold pain sensitivity in 461 healthy patients who were scheduled to undergo cosmetic orthognathic surgery for mandibular prognathism. We found an association between cold pain sensitivity and the rs2243057 polymorphism of the PAR2 gene. We also found a significant association between cold pain sensitivity and the rs12992084 polymorphism of the TRPM8 gene. Carriers of the minor A allele of the rs2243057 polymorphism of PAR2 and minor C allele of the rs12992084 polymorphism of TRPM8 exhibited a longer latency to pain perception in the cold-induced pain test, reflecting a decrease in cold pain sensitivity. These results suggest that genetic polymorphisms of both PAR2 and TRPM8 are involved in individual differences in cold pain sensitivity.

Functional Coupling between the P2X7 Receptor and Pannexin-1 Channel in Rat Trigeminal Ganglion Neurons.

The ionotropic P2X receptor, P2X7, is believed to regulate and/or generate nociceptive pain, and pain in several neuropathological diseases. Although there is a known relationship between P2X7 receptor activity and pain sensing, its detailed functional properties in trigeminal ganglion (TG) neurons remains unclear. We examined the electrophysiological and pharmacological characteristics of the P2X7 receptor and its functional coupling with other P2X receptors and pannexin-1 (PANX1) channels in primary cultured rat TG neurons, using whole-cell patch-clamp recordings. Application of ATP and Bz-ATP induced long-lasting biphasic inward currents that were more sensitive to extracellular Bz-ATP than ATP, indicating that the current was carried by P2X7 receptors. While the biphasic current densities of the first and second components were increased by Bz-ATP in a concentration dependent manner; current duration was only affected in the second component. These currents were significantly inhibited by P2X7 receptor antagonists, while only the second component was inhibited by P2X1, 3, and 4 receptor antagonists, PANX1 channel inhibitors, and extracellular ATPase. Taken together, our data suggests that autocrine or paracrine signaling via the P2X7-PANX1-P2X receptor/channel complex may play important roles in several pain sensing pathways via long-lasting neuronal activity driven by extracellular high-concentration ATP following tissue damage in the orofacial area.

Stage-dependent differential gene expression profiles of cranial neural crest-like cells derived from mouse-induced pluripotent stem cells.

Cranial neural crest cells are multipotent cells that migrate into the pharyngeal arches of the vertebrate embryo and differentiate into various craniofacial organ derivatives. Therefore, migrating cranial neural crest cells are considered one of the most attractive candidate cell sources in regenerative medicine. We generated cranial neural crest like cell (cNCCs) using mouse-induced pluripotent stem cells cultured in neural crest-inducing medium for 14 days. Subsequently, we conducted RNA sequencing experiments to analyze gene expression profiles of cNCCs at different time points after induction. cNCCs expressed several neural crest specifier genes; however, some previously reported specifier genes such as paired box 3 and Forkhead box D3, which are essential for embryonic neural crest development, were not expressed. Moreover, ETS proto-oncogene 1, transcription factor and sex-determining region Y-box 10 were only expressed after 14 days of induction. Finally, cNCCs expressed multiple protocadherins and a disintegrin and metalloproteinase with thrombospondin motifs enzymes, which may be crucial for their migration.

Acupuncture Combined with Trigger Point Injection in Patient with Chronic Myofascial and Referred Pain.

Here, we report a case in which acupuncture combined with trigger point injection was effective in a patient with chronic myofascial pain with referred pain in the masticatory muscles. The patient was a 46-year-old woman with the chief complaint of chronic persistent pain in the region of the left mandibular first molar, which had been extracted 5 months earlier. Stellate ganglion block was performed and amitriptyline administered at another hospital, but were ineffective. At her initial visit to our hospital, her primary complaint was chronic persistent pain in the region of the bilateral mandibular first molars. Several tender points were found on the masseter, temporalis, and sternocleidomastoid muscles, with bilateral referred pain. The pain score according to the visual analogue scale was 85. No significant psychological factors were found, however. Based on these findings, the diagnosis was chronic myofascial pain with referred pain in the masticatory muscles. Therefore, stretching of masticatory muscle and trigger point injection were performed. Two months later, the patient requested trigger point injections to be performed at all tender points, as the previous injections had been effective. The total volume of local anesthetic that this would require was considered to be excessive as there was a large number of tender points, however, and it was feared that a toxic reaction might occur. Therefore, acupuncture in combination with trigger point injection was selected instead. The symptoms disappeared within 9 months after commencement of this therapy, and treatment was completed within 1 year. The present results suggest that acupuncture therapy is effective when used in combination with trigger point injection.

Decreases in Oral Tissue Blood Flow Induced by Remifentanil Are Not Accompanied by Deterioration of Oral Tissue Oxygen Tension in Rabbits.

PURPOSE: The purpose of this study was to investigate the effects of remifentanil infusion on tissue blood flow and tissue oxygen tension in the mandibular bone marrow and masseter muscle in rabbits. In addition, changes in tissue oxygen consumption in those tissues during remifentanil infusion were investigated. MATERIALS AND METHODS: Sixteen male tracheotomized Japanese White rabbits were anesthetized with sevoflurane under mechanical ventilation. Under oxygen and air inhalation, fraction of inspiratory oxygen was set at 0.4 and remifentanil was infused at a rate of 0.4 µg ∙ kg-1 ∙ min-1. Measurements were performed before remifentanil infusion, 20 minutes after the start of remifentanil infusion, and 20 and 60 minutes after the completion of remifentanil infusion (n = 8). The observed variables included heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), mandibular bone marrow tissue blood flow (BBF), masseter muscle tissue blood flow (MBF), mandibular bone marrow tissue oxygen tension (PbO2), and masseter muscle tissue oxygen tension (PmO2). Another 8 rabbits were observed for arterial pH, lactate, base excess (BE), and tissue oxygen consumption in the region from which the retromandibular vein received venous blood. Measurements were performed before remifentanil infusion and 20 minutes after the start of remifentanil infusion. RESULTS: HR, SBP, DBP, MAP, BBF, and MBF decreased during remifentanil infusion. PbO2 increased 20 minutes after remifentanil infusion and returned to almost the baseline value 60 minutes after remifentanil infusion. PmO2 did not change throughout the experiment. The difference between the arterial oxygen content of the femoral artery and the venous oxygen content of the retromandibular vein decreased during remifentanil infusion. Arterial pH, lactate, and BE did not change during remifentanil infusion. CONCLUSIONS: Remifentanil decreased BBF and MBF but did not decrease PbO2 and PmO2. It is suggested that tissue oxygen consumption decreased during remifentanil infusion.

Genome-wide association study identifies polymorphisms associated with the analgesic effect of fentanyl in the preoperative cold pressor-induced pain test.

Opioid analgesics are widely used for the treatment of moderate to severe pain. The analgesic effects of opioids are well known to vary among individuals. The present study focused on the genetic factors that are associated with interindividual differences in pain and opioid sensitivity. We conducted a multistage genome-wide association study in subjects who were scheduled to undergo mandibular sagittal split ramus osteotomy and were not medicated until they received fentanyl for the induction of anesthesia. We preoperatively conducted the cold pressor-induced pain test before and after fentanyl administration. The rs13093031 and rs12633508 single-nucleotide polymorphisms (SNPs) near the LOC728432 gene region and rs6961071 SNP in the tcag7.1213 gene region were significantly associated with the analgesic effect of fentanyl, based on differences in pain perception latency before and after fentanyl administration. The associations of these three SNPs that were identified in our exploratory study have not been previously reported. The two polymorphic loci (rs13093031 and rs12633508) were shown to be in strong linkage disequilibrium. Subjects with the G/G genotype of the rs13093031 and rs6961071 SNPs presented lower fentanyl-induced analgesia. Our findings provide a basis for investigating genetics-based analgesic sensitivity and personalized pain control.

Comparison of Changes in Respiratory Dynamics Immediately After the Start of Propofol Sedation With or Without Midazolam.

PURPOSE: The aim of this study was to compare changes in respiratory dynamics starting immediately after administration of propofol alone or a combination of propofol and midazolam. MATERIALS AND METHODS: Twenty-seven healthy adult volunteers participated in a randomized crossover study of undergoing sedation with propofol alone (P group) or with a combination of propofol and midazolam (PM group). In the P group, continuous infusion of propofol through a target-controlled infusion (TCI) pump was started with the target effect site (ES) concentration set at 1.2 µg/mL. In the PM group, participants received a bolus administration of midazolam 0.02 mg/kg simultaneously with the start of continuous infusion of propofol through a TCI pump with the target ES concentration set at 0.8 µg/mL. The variables measured included the bispectral index (BIS) value, tidal volume (VT), percutaneous arterial oxygen saturation (SpO2), respiratory rate (RR), end-tidal carbon dioxide tension (ETCO2), estimated ES propofol concentration, and minute volume. RESULTS: BIS value, VT, SpO2, and ETCO2 decreased after sedative administration in the 2 groups. RR increased in the 2 groups. These changes occurred sooner in the PM group than in the P group. The ratio of change in VT to change in BIS value decreased in the 2 groups and was markedly smaller in the PM group than in the P group. Ratios of changes in SpO2, RR, and ETCO2 to change in BIS value increased in the 2 groups and were larger in the PM group than in the P group. CONCLUSION: Changes in respiratory dynamics occurred sooner in the PM group than in the P group. In the PM group, although VT began to decrease before the change in BIS value, the increase in RR caused the rate of decrease in SpO2 to be smaller than the rate of decrease in BIS value.