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.

Heparan sulfate 3-O-sulfotransferase 4 is genetically associated with herpes zoster and enhances varicella-zoster virus-mediated fusogenic activity.

Acute pain that is associated with herpes zoster (HZ) can become long-lasting neuropathic pain, known as chronic post-herpetic neuralgia (PHN), especially in the elderly. HZ is caused by the reactivation of latent varicella-zoster virus (VZV), whereas PHN is not attributed to ongoing viral replication. Although VZV infection reportedly induces neuronal cell fusion in humans, the pathogenesis of PHN is not fully understood. A genome-wide association study (GWAS) revealed significant associations between PHN and the rs12596324 single-nucleotide polymorphism (SNP) of the heparan sulfate 3-O-sulfotransferase 4 (HS3ST4) gene in a previous study. To further examine whether this SNP is associated with both PHN and VZV reactivation, associations between rs12596324 and a history of HZ were statistically analyzed using GWAS data. HZ was significantly associated with the rs12596324 SNP of HS3ST4, indicating that HS3ST4 is related to viral replication. We investigated the influence of HS3ST4 expression on VZV infection in cultured cells. Fusogenic activity after VZV infection was enhanced in cells with HS3ST4 expression by microscopy. To quantitatively evaluate the fusogenic activity, we applied cytotoxicity assay and revealed that HS3ST4 expression enhanced cytotoxicity after VZV infection. Expression of the VZV glycoproteins gB, gH, and gL significantly increased cytotoxicity in cells with HS3ST4 expression by cytotoxicity assay, consistent with the fusogenic activity as visualized by fluorescence microscopy. HS3ST4 had little influence on viral genome replication, revealed by quantitative real-time polymerase chain reaction. These results suggest that HS3ST4 enhances cytotoxicity including fusogenic activity in the presence of VZV glycoproteins without enhancing viral genome replication.

Genome-wide association study identifies candidate loci associated with chronic pain and postherpetic neuralgia.

BACKGROUND: Human twin studies and other studies have indicated that chronic pain has heritability that ranges from 30% to 70%. We aimed to identify potential genetic variants that contribute to the susceptibility to chronic pain and efficacy of administered drugs. We conducted genome-wide association studies (GWASs) using whole-genome genotyping arrays with more than 700,000 markers in 191 chronic pain patients and a subgroup of 89 patients with postherpetic neuralgia (PHN) in addition to 282 healthy control subjects in several genetic models, followed by additional gene-based and gene-set analyses of the same phenotypes. We also performed a GWAS for the efficacy of drugs for the treatment of pain. RESULTS: Although none of the single-nucleotide polymorphisms (SNPs) were found to be genome-wide significantly associated with chronic pain (p ≥ 1.858 × 10-7), the GWAS of PHN patients revealed that the rs4773840 SNP within the ABCC4 gene region was significantly associated with PHN in the trend model (nominal p = 1.638 × 10-7). In the additional gene-based analysis, one gene, PRKCQ, was significantly associated with chronic pain in the trend model (adjusted p = 0.03722). In the gene-set analysis, several gene sets were significantly associated with chronic pain and PHN. No SNPs were significantly associated with the efficacy of any of types of drugs in any of the genetic models. CONCLUSIONS: These results suggest that the PRKCQ gene and rs4773840 SNP within the ABCC4 gene region may be related to the susceptibility to chronic pain conditions and PHN, respectively.

Temperature-dependent inotropic and lusitropic indices based on half-logistic time constants for four segmental phases in isovolumic left ventricular pressure-time curve in excised, cross-circulated canine heart.

Varying temperature affects cardiac systolic and diastolic function and the left ventricular (LV) pressure-time curve (PTC) waveform that includes information about LV inotropism and lusitropism. Our proposed half-logistic (h-L) time constants obtained by fitting using h-L functions for four segmental phases (Phases I-IV) in the isovolumic LV PTC are more useful indices for estimating LV inotropism and lusitropism during contraction and relaxation periods than the mono-exponential (m-E) time constants at normal temperature. In this study, we investigated whether the superiority of the goodness of h-L fits remained even at hypothermia and hyperthermia. Phases I-IV in the isovolumic LV PTCs in eight excised, cross-circulated canine hearts at 33, 36, and 38 °C were analyzed using h-L and m-E functions and the least-squares method. The h-L and m-E time constants for Phases I-IV significantly shortened with increasing temperature. Curve fitting using h-L functions was significantly better than that using m-E functions for Phases I-IV at all temperatures. Therefore, the superiority of the goodness of h-L fit vs. m-E fit remained at all temperatures. As LV inotropic and lusitropic indices, temperature-dependent h-L time constants could be more useful than m-E time constants for Phases I-IV.

[The Prevention and Management of Complications and Side Effects of Pain Treatment: Preface and Comments].

Methods of pain treatment are various because of different mechanisms and causes of pain. However, we should recognize complications and side effects of these methods of pain treatment. In addition, we should understand the prevention and management of these complications and side effects. If patients develop side effects during pain treatment they may hesitate to continue to receive pain treatment. We must avoid these situations. In this special issue, the prevention and management of complications and side effects of pain treatment are described including nerve block such as stellate ganglion block, epidural block and nerve root block, and interventional methods such as spinal cord stimulation, thermocoagulation and pulse radiofrequency. Concerning drugs, opioid, non-opioid analgesics, antidepressants and anticoagulant are also discussed.

Half-Logistic Function Model for First Half of Descending Phase of Cardiomyocyte Cytoplasmic Ca(2+) Concentration ([Ca(2+)]i)-Time Curve (CaTCIII) in Isolated Aequorin-Injected Mouse Left Ventricular Papillary Muscle.

BACKGROUND: Myocardial contraction and relaxation are regulated by increases and decreases in cytoplasmic calcium concentration ([Ca(2+)]i). In previous studies, we found that a half-logistic (h-L) function, which represents a half-curve of a symmetrical sigmoid logistic function with a boundary at the inflection point, curve-fits the first half of the ascending phase and the second half of the descending phase of the [Ca(2+)]i transient curve better than a mono-exponential (m-E) function. In the present study, we investigated the potential application of an h-L function to analyse the first half of the descending phase of CaTC (CaTCIII). METHODS: The [Ca(2+)]i was measured using the Ca(2+)-sensitive aequorin, which was microinjected into 15 isolated mouse left ventricular (LV) papillary muscles. The observed CaTCIII data in the interval from the point corresponding to the peak [Ca(2+)]i to the point corresponding to dCa/dtmin was curve-fitted using the h-L and m-E function equations by the least-squares method. RESULTS: The mean correlation coefficient (r) values of the h-L and m-E function best curve-fits for 11 CaTCIIIs were 0.9986 and 0.9982, respectively. The Z transformation of h-L r (3.64 ± 0.45) was larger than that of m-E r (3.50 ± 0.33) (p < 0.05). CONCLUSIONS: The h-L function can evaluate most CaTCIIIs more accurately than the m-E function in isolated aequorin-injected mouse LV papillary muscle. The three calculated h-L parameters i.e., amplitude constant, time constant, and non-zero asymptote, are more reliable indices than m-E for evaluating the magnitude and time course of the change in the decrease in [Ca(2+)]i. KEY WORDS: Ca(2+) transient; Half-logistic amplitude constant; Half-logistic non-zero asymptote; Half-logistic time constant; Myocardial Ca(2+) handling.

[Past contributions to anesthesiology by Japanese anesthesiologists].

This article describes the first events of general anesthesia in the world by Tokumei Takamine in 1698 and Seishu Hanaoka in 1804, the establishment of anesthesiology in Japan including the meaning of a scientific society, the establishment of Japanese Society of Anesthesiologist and Department of Anesthesiology at University of Tokyo, past contributions to anesthesiology by Japanese anesthesiologists, and contributions to anesthesiology by Journal of Anesthesia and the Japanese Journal of Anesthesiology.

[Rehabilitation for Pain Relief: Preface and Comments].

Chronic intractable pain is difficult to manage as the mechanisms of chronic pain are complicated. Recently rehabilitation is used in patients with chronic pain not responding to NSAIDs, non-opioids, anti-depressants and so on. Rehabilitation includes acute, recovery and maintained modes of rehabilitation. This review is focused on the concept of rehabilitation, rehabilitation therapy, rehabilitation during recovery period, nerve rehabilitation, music-trampoline therapy and so on.

[Transdermal Local Anesthetics].

Taking EMLA cream and Penles tape 18 mg as examples, this article describes the conditions for skin penetration of topical anesthetics, with their onset time of action, duration of effect and a precautions for their use. EMLA cream is a unique cream for topical anesthesia which is the eutectic mixture of lidocaine and propitocaine to increase skin penetration. The safety study demonstrated that blood concentrations of active ingredients of EMLA cream were below toxic levels. EMLA cream, with confirmed high skin penetrability and safety, should be used for pain reduction of various treatments for many diseases. Here in Japan, EMLA cream has indications not only for pain reduction of skin laser therapy but also for reduction of needle puncture pain. This means the use of topical anesthesia would be expanded to wider ranges of treatments.

[Diagnostic and therapeutic devices for patients with chronic intractable pain: preface and comments].

New diagnostic and therapeutic devices for patients with chronic intractable pain are used in Japan. The following articles describe topics of new diagnostic and therapeutic devices for patients with chronic intractable pain including thermography, functional MRI, device for the quantitative analysis of perception and pain sensation, epiduroscopy, device for phototherapy, Racz catheter and device for spinal cord stimulation (SCS).

[Device for quantitative analysis of perception and pain sensation].

The article describes an analysing device that measures the perception and intensity of pain quantitatively. While it is not necessarily true that psychological aspect is totally irrelevant to pain measurement, this device is remarkable in that it is capable of measuring the intensity of pain felt by the patient more objectively by using electric stimuli. The feature of this device is that it uses a non-pain heteresthesia for measuring the intensity of pain. The device is compact, light-weight, and portable. Unlike VAS that requires only a scale, the device requires a person to carry out the measurement. Nevertheless, as the National Health Insurance (NHI) coverage has been approved, introduction of the device may be facilitated in terms of budget for the purchase and labor. The device is useful to better understand not only the intensity of pain but also the pathological conditions, resulting in more appropriate treatment, by (1) comparing degree of pain or VAS values taken by a multicenter study with those of a patient; (2) using both degree of pain and VAS; and (3) multiple measurements of degree of pain and VAS in one case.

[New drug therapies for intractable chronic pain: preface and comments].

Recently, new drugs for intractable chronic pain are available in Japan. The following articles describe topics of new drugs for intractable chronic pain including transdermal fentanyl, tramadol/acetaminophen combination tablets, buprenorphine transdermal patch, pregabalin, and duloxetine. Treatment of constipation in chronic pain patients and management of opioid induced nausea and vomiting are also described to prevent complication of pain-relief drug therapy.

[Perioperative management in children with sleep apnea syndrome (SAS) undergoing adenoidotonsillectomy].

We should take care of the occurrences of apnea and hypopnea after emergence from general anesthesia in the children with sleep apnea syndrome (SAS) due to an increase in sensitivity to opioid agonists given for previous recurrent hypoxia. Preoperative assessment for SAS with apnea hypopnea index (AHI), oxygen desaturation index (ODI), and minimum artery oxygen saturation by pulse oxymetry (lowest SpO2) obtained from polysomnography (PSG) test could help to predict the postoperative respiratory depression. In perioperative management in the children with SAS who are candidates for adenotonsillectomy, the dose of opioid agonists during anesthesia maintenance for purpose of postoperative analgesia and sedation should be reduced; postoperative respiratory and circulatory management with monitoring of respiratory movement of the thoracoabdominal part, and electrographic (ECG) and SpO2 monitoring should be continued intensively under long-term oxygen administration; and airway management, nasal continuous positive airway pressure (nCPAP), and artificial ventilation should be prepared for the occurrence of postoperative respiratory depression.

Intracellular Ca(2+) Transient Phase II Can be Assessed by Half-Logistic Function Model in Isolated Aequorin-Injected Mouse Left Ventricular Papillary Muscle.

BACKGROUND: Myocardial contraction and relaxation are regulated by increases and decreases in intracellular cytoplasmic calcium (Ca(2+)) concentration ([Ca(2+)]i). In previous studies, we found that a half-logistic (h-L) function, which represents a half-curve of a symmetrical sigmoid logistic function with a boundary at the inflection point, curve-fits the first half of the ascending phase (CaTI) and the second half of the descending phase of the [Ca(2+)]i transient curve (CaTIV) better than a mono-exponential (m-E) function. In the present study, we investigated the potential application of an h-L function to the analysis of the second half of the ascending phase of the [Ca(2+)]i transient curve (CaTII). METHODS: The [Ca(2+)]i transient was measured using the Ca(2+)-sensitive photoprotein aequorin, which was microinjected into 15 isolated left ventricular (LV) papillary muscles of mice. The observed CaTII data during the time duration from the point corresponding to the maximum of the first-order time derivative of Ca(2+) concentration (dCa/dtmax) to the point corresponding to the peak Ca(2+) concentration was curve-fitted by the least-squares method using the h-L and m-E function equations. RESULTS: The mean correlation coefficient (r) values of the h-L and m-E curve-fits for CaTII were 0.9996 and 0.9984, respectively. The Z transformation of h-L r was larger than that of m-E r (p < 0.0001). H-L residual mean square (RMS) was smaller than m-E RMS (p < 0.001). CONCLUSIONS: The h-L function tracks the magnitudes and time courses of CaTII more accurately than the m-E function in isolated aequorin-injected mouse LV papillary muscle. Compared with the m-E time constant, the h-L time constant of CaTII is a more reliable index for evaluating the time duration of the change in the increase in [Ca(2+)]i during the combination of the middle part of the contraction process and the early part of the relaxation process. CaTII can be assessed by the h-L function model in cardiac muscles. The h-L approach may provide a more useful model for studying each process in myocardial Ca(2+) handling. KEY WORDS: Calcium handling; Calcium transient; Curve-fit; Half-Logistic function; Time constant.

[Usefulness and clinical application of phototherapy: preface and comments].

The following articles describe topics of phototherapy including low reactive laser therapy by diode laser device, semiconductor as a medium consisting of aluminum, gallium and arsenic, near infrared light irradiator using halogen lamp, and xenon light by high-intensity electrical stimulation of xenon gas. In addition, the applications of phototherapy in the clinical medicine such as rehabilitation, orthopedics and pain clinic are described. Phototherapy is a useful and safe method for pain relief.

Pentazocine-induced antinociception is mediated mainly by µ-opioid receptors and compromised by κ-opioid receptors in mice.

Pentazocine is a widely used mixed agonist-antagonist opioid. Previous animal studies have demonstrated that pentazocine-induced antinociception displayed a ceiling effect characterized by biphasic dose response with a increasing and then descending analgesia like a bell-shaped curve. This study attempted to clarify the mechanisms underlying such dose-response relationships. ddY and C57BL/6J mice received subcutaneous injection of saline or pentazocine (3, 10, 30, 56, or 100 mg · kg(-1)), at 120 min after subcutaneous injection of saline, a µ-opioid receptor antagonist clocinnamox mesylate (C-CAM) (5 mg · kg(-1)), a κ-opioid receptor antagonist nor-binaltorphimine (nor-BNI) (10 mg · kg(-1)), or the combination of C-CAM and nor-BNI. The antinociceptive effects of pentazocine were evaluated using tail pressure, hot plate, tail flick, and acetic acid writhing tests. Without pretreatment with an opioid receptor antagonist, the antinociceptive effects of pentazocine exhibited biphasic bell-shaped dose-response curves peaking at 30 mg · kg(-1). C-CAM completely and partly antagonized the antinociception induced by pentazocine at low (3-30 mg · kg(-1)) and high (56-100 mg · kg(-1)) doses, respectively. nor-BNI enhanced the antinociception by pentazocine at high doses and turned the later descending portion of the biphasic dose-response curves into a sigmoid curve. The combination of C-CAM and nor-BNI completely abolished the antinociception by pentazocine at all doses. Our results suggest pentazocine produces antinociception primarily via activation of µ-opioid receptors, but at high doses, this µ-opioid receptor-mediated antinociception is antagonized by concomitant activation of κ-opioid receptors. This provides the first reasonable hypothesis to explain the ceiling effects of pentazocine analgesia characterized by a biphasic dose response.

Calcium-induced calcium release from the sarcoplasmic reticulum can be evaluated with a half-logistic function model in aequorin-injected cardiac muscles.

PURPOSE: Release of calcium (Ca(2+)) from the sarcoplasmic reticulum (SR) induced by Ca(2+) influx through voltage-dependent sarcolemmal L-type Ca(2+) channels (CICR) in cardiac muscle cells has been implicated as a potential target contributing to anesthetic-induced myocardial depression. In an earlier study, we found that (1) a half-logistic (h-L) function, which represents a half-curve of a sigmoid logistic function with a boundary at the inflection point, curve-fits the first half of the ascending phases of the isometric myocardial tension and isovolumic left ventricular (LV) pressure waveforms better than a mono-exponential (m-E) function and (2) the h-L time constants are useful as inotropic indices. We report here our investigation of the potential application of an h-L function to the analysis of the first half of the ascending phase of the Ca(2+) transient curve (faCaT) that precedes and initiates myocardial contraction and the increase in LV pressure. METHODS: Ca(2+) transients (CaT) were measured using the Ca(2+)-sensitive photoprotein aequorin, which was microinjected into seven isolated rabbit right ventricular and 15 isolated mouse LV papillary muscles. The faCaT data from the beginning of twitch stimulation to the maximum of the first-order time derivative of Ca(2+) concentration (dCa/dt(max)) was curve-fitted by the least-squares method using h-L and m-E function equations. RESULTS: The mean correlation coefficient (r) values of the h-L and m-E curve-fits for the faCaTs were 0.9740 and 0.9654 (P < 0.05) in the rabbit and 0.9895 and 0.9812 (P < 0.0001) in the mouse. CONCLUSION: The h-L curves tracked the amplitudes and time courses of the faCaTs in cardiac muscles more accurately than m-E functions. Based on this result, we suggest that the h-L time constant may be a more reliable index than the m-E time constant for evaluating the rate of CICR from the SR in myocardial Ca(2+) handling. The h-L approach may provide a more useful model for the study of CICR during the contraction process induced by anesthetic agents.

[Cancer pain and evaluation of the pain: preface and comments].

Cancer pain is very unpleasant often difficult to treat. Therefore, we should recognize the mechanisms of cancer pain and know the physical pain, psychological pain, social pain and spiritual pain as total pain. Besides, we must understand how to evaluate the cancer pain using the methods of assessment of cancer pain, and scales of pain degree (VAS, NRS, VRS, FRS, FVAS). New devices of pain measurement and the character of pain(McGill and Yatabe) are also introduced. The mechanism and grade of cancer pain often confuse us to recognize cancer pain. The articles in this special issue are useful for the evaluation and treatment of cancer pain. I feel happy if these articles contribute to the treatment of patients with cancer pain.

[Physical pain in advanced cancer].

This chapter describes physical pain including pain, anorexia-cachexia syndrome, nausea-vomiting, abdominal distention, ascites, constipation and dyspnea. In effect, patients are more likely to present with several concurrent symptoms. Each of these symptoms is described separately in this chapter.