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CACNG2 polymorphisms associate with chronic pain following mastectomy
Abstract
Chronic postmastectomy pain (PMP) imposes a major burden on the quality of life of the ever-increasing number of long-term survivors of breast cancer. An earlier report by Nissenbaum et al. (2010) claimed that particular polymorphisms in the gene CACNG2 are associated with the risk of developing chronic PMP after breast surgery. This information is important as in principle it can inform the surgical, radiological and chemotherapeutic decision-making process in ways that could mitigate the increased risk of chronic pain. In the present study we revisited this claim by independently evaluating the proposed marker haplotype using two different patient cohorts recruited in different research settings. Meta-analysis of these new postmastectomy cohorts and the original cohort confirmed significant association of the CACNG2 haplotype with PMP. In addition, we tested whether the same markers would predict chronic postsurgical pain in men who underwent surgery for inguinal hernia repair, and whether there is significant genetic association with cutaneous thermal sensitivity in postmastectomy and postherniotomy patients. We found that the biomarker is selective as it did not predict pain following laparoscopic hernia repair and was not associated with pain sensitivity to experimentally applied noxious thermal stimuli. We conclude that the A-C-C haplotype at the three single nucleotide polymorphisms (rs4820242, rs2284015 and rs2284017) in the CACNG2 gene is associated with increased risk of developing PMP. This information may advance current knowledge on pathophysiology of PMP and serve as a step forward prediction of clinical outcomes and personalized pain management.
... Like neuropathic pain, epilepsy is the result of neuronal hyperexcitability 10 . Nissenbaum et al 11 and Borstov et al 12 identified the association of the homozygous ACC haplotype of CACNG2 gene single nucleotide polymorphisms (SNPs) rs4820242, rs2284015 and rs2284017 with the tendency to develop neuropathic pain after breast cancer surgery [Odds ratio (OR) 1.65, p = 0.001 and OR 1.40, p = 0.033, respectively]. Bortsov et al 12 did not observe an association of the ACC haplotype with the risk of post-herniotomy chronic pain in male patients (OR 0.97, p = 0.90), but they did observe an association in the opposite direction (OR 0.55, p = 0.024) of that reported by Nissenbaum et al 8 ...
... Nissenbaum et al 11 and Borstov et al 12 identified the association of the homozygous ACC haplotype of CACNG2 gene single nucleotide polymorphisms (SNPs) rs4820242, rs2284015 and rs2284017 with the tendency to develop neuropathic pain after breast cancer surgery [Odds ratio (OR) 1.65, p = 0.001 and OR 1.40, p = 0.033, respectively]. Bortsov et al 12 did not observe an association of the ACC haplotype with the risk of post-herniotomy chronic pain in male patients (OR 0.97, p = 0.90), but they did observe an association in the opposite direction (OR 0.55, p = 0.024) of that reported by Nissenbaum et al 8 ...
... The homozygous ACC haplotype of CACNG2 rs4820242, rs2284015 and rs2284017 constitutes a risk factor for chronic neuropathic pain in women undergoing mastectomy 8,11,12 , while the C allele of rs2284015 is a factor that reduces the risk of neuropathic pain in men undergoing herniotomy 12 . The genetic structure can have variations in different populations. ...
Objective:
In animal models and humans, mutations in voltage-dependent calcium channel gamma-2 subunit gene (CACNG2) have been associated with neuronal hyperexcitability, including neuropathic pain. The objective of this study was to determine the allelic and genotypic frequencies of CACNG2 polymorphisms (rs4820242, rs2284015 and rs2284017) and their association with the risk of chronic peripheral neuropathic pain (CPNP) in the Mexican population.
Patients and methods:
Single nucleotide polymorphisms (SNPs) were determined by real-time PCR, and allelic and genotypic frequencies were compared between healthy Mexican subjects and CPNP patients. The risk of association of CACNG2 SNPs with the presence of CPNP and its characteristics was evaluated.
Results:
The allele G (OR 2.08, p = 0.01) of rs2284015 was observed as a risk factor for developing CPNP. The allele A of rs4820442 showed a risk of association with a history of surgery (OR 3.92, p = 0.04), radiculopathy (OR 4.29, p = 0.0001), bilateral presentation of pain (OR 3.15, p = 0.003), and neuropraxia (OR 0.36, p = 0.01). The allele C of rs2284015 was associated with an increased risk of burning and allodynia. In the analysis of the association of genotype frequencies and inheritance patterns, as well as in the analysis of interaction with sex, a modification of risk was observed.
Conclusions:
The allele G of rs2284015 and the AGC haplotype of CACNG2 rs4820242, rs2284015 and rs2284017, regardless of sex and etiology could contribute to the risk of CPNP. Certain alleles and genotypes could constitute severity markers in CPNP with sex-biased effects; however, further studies are required to confirm these observations.
... In recent years, plenty of studies focused on the potential mechanism of neuropathic pain, [10][11][12] but most of them only restricted to dorsal root ganglia (DRG) without the involvement of spinal cord like dorsal horns. 13 Meanwhile, it was verified that hundreds of pain-related genes existed substantial expression changes in the spinal cord tissue, and most of these genes were tested in neuronal, instead of microglial. ...
... IL-1β is an essential mediator in microglia after activating the p38 pathway, which can further regulate presynaptic and post-synaptic function by affecting the N-methyl-D-aspartic acid receptor (NMDAR). 10,29 Furthermore, the KEGG pathway analysis result revealed that DEGs were mainly enriched in malaria inflammatoryrelated pathway and Toll-like receptor signal pathway, which were consistent with the BP term in GO annotation. ...
Purpose:
Neuropathic pain is a devastating complex condition occurring post-nervous system damage. Microglia in dorsal horn drives neuropathic pain as a kind of immune cell. We aimed to find potential differentially expressed genes (DEGs) and candidate pathways, which induced neuropathic pain, and to identify some new transcription factors and therapeutic drugs via bioinformatic analysis.
Methods:
The microarray profile GSE60670 was downloaded and analyzed. DEGs were screened and analyzed through Gene Ontology (GO), pathway enrichment, and protein-to-protein interaction (PPI) network. Respectively, transcription factors (TFs) and potential therapeutic drugs for DEGs were predicted through NetworkAnalyst and DGIdb databases. At last, we chose top 10 DEGs for external validation.
Results:
A total of 100 DEGs were identified. The results of pathway and GO analyses were closely related to malaria inflammatory pathway and inflammatory response. Three necessary PPI modules and 9 hub genes were identified in PPI analysis, and 277 DEG-TF pairs were found among 54 DEGs and 32 TF. Moreover, 22 candidate drugs were found to match 9 hub genes. External validation of 9 of the top 10 DEGs were consistent with bioinformatic analysis.
Conclusion:
This study provided comprehensive analyses for the functional gene sets and pathways related to neuropathic pain and promoted our understanding of the mechanism or therapy of neuropathic pain.
... Currently, rare studies are devoted to identifying biomarkers of PNS damage in women who survived breast cancer. In addition, few works analyze the polymorphism of genes that may be associated with chronic pain syndrome after breast cancer [16][17][18]. ...
Damage to the peripheral nervous system (PNS) is a common complication of breast cancer (BC) treatment, with 60 to 80% of breast cancer survivors experiencing symptoms of PNS damage. In the current study, the levels of brain-derived neurotrophic factor (BDNF), galectin-3 (Gal-3), and neurotrophin-3 (NT-3) were measured in the blood serum of BC patients by ELISA as potential biomarkers that might indicate the PNS damage. Sixty-seven patients were enrolled in this multi-center trial and compared to the aged-matched healthy female volunteers (control group) (n = 25). Intergroup comparison of biomarker levels (i.e., Gal-3 and BDNF) did not show significant differences in any of the studied subgroups. However, intriguingly, NT-3 levels were significantly higher in BC patients as compared to healthy volunteers, constituting 14.85 [10.3; 18.0] and 5.74 [4.56; 13.7] pg/mL, respectively (p < 0.001). In conclusion, NT-3 might be employed as a potential biomarker in BC patients with clinical manifestations of PNS damage. However, further studies to validate its correlation to the degree of peripheral nervous system lesions are of high value.
... These findings provide new insights into the actin regulatory mechanisms of neuronal development, revealing potential pathways that are disrupted in many neurological disorders [32]. CACNG2 can affect the susceptibility to postoperative chronic pain [33] or chronic pain caused by nerve injury [34]. Existing research shows that elevated expression levels of PLOD3 can accelerate tumor progression and indicate poor prognosis [35], which is consistent with our signature where the weight of PLOD3 was positive. ...
Background
Glioblastoma is one of the most common brain cancers in adults, and is characterized by recurrence and little curative effect. An effective treatment for glioblastoma patients remains elusive worldwide. 7-methylguanosine (m7G) is a common RNA modification, and its role in tumors has become a research hotspot.
Methods
By searching for differentially expressed genes related to m7G, we generated a prognostic signature via cluster analysis and established classification criteria of high and low risk scores. The effectiveness of classification was validated using the Non-negative matrix factorization (NMF) algorithm, and repeatedly verified using training and test groups. The dimension reduction method was used to clearly show the difference and clinical significance of the data. All analyses were performed via R (version 4.1.2).
Results
According to the signature that included four genes (TMOD2, CACNG2, PLOD3, and TMSB10), glioblastoma patients were divided into high and low risk score groups. The survival rates between the two groups were significantly different, and the predictive abilities for 1-, 3-, and 5-year survivals were effective. We further established a Nomogram model to further examine the signature,as well as other clinical factors, with remaining significant results. Our signature can act as an independent prognostic factor related to immune-related processes in glioblastoma.
Conclusions
Our research addresses the gap in knowledge in the m7G and glioblastoma research fields. The establishment of a prognostic signature and the extended analysis of the tumor microenvironment, immune correlation, and tumor mutation burden further suggest the important role of m7G in the development and development of this disease. This work will provide support for future research.
... Additionally, Cacng2 variants (Cacng2 encodes for the y2 transmembrane AMPA receptor protein stargazin) affect susceptibility to chronic pain after nerve injury in mice (Neely et al., 2010). In humans, an association was observed between increased susceptibility to pain after mastectomy and the A-C-C haplotype constructed from the CACNA2 rs4820242, rs2284015, and rs2284017 intronic variants (Bortsov et al., 2019). ...
The mechanisms of pain in tendinopathy are unclear. Current theories implicate tendon structural changes, neovascularisation, inflammation or changes in central pain processing. As with other types of musculoskeletal pain, tendon pain has high interindividual variability and, as with other types of pain, this could be attributed to genetic variation. Notably, the association between certain genetic polymorphisms and susceptibility to tendinopathy is well established in the literature. Therefore, the investigation of the mechanisms of tendon pain should also extend to include genetic variation as a possible explanation for the clinical features of tendon pain. This review summarises the current knowledge on genetic contributors to chronic pain and highlights findings that are relevant to chronic tendon pain. In particular, based on the current hypotheses on the possible sources of tendon pain, it focuses on findings that relate to genes that encode structural connective tissue components, inflammatory markers, ion channels and catecholamines and how they may relate to chronic tendon pain. In the absence of a definitive mechanism of tendon pain, an a priori genetic approach that is guided by these current hypotheses may help elucidate the mechanisms of tendon pain which may allow a more rational approach to research and treatment.
... A more recent meta-analysis conducted on two cohorts of women confirmed a relationship between polymorphism in the gene CACNG2 and chronic pain after breast surgery. The authors of the meta-analysis concluded that the A-C-C haplotype at three single-nucleotide polymorphisms (rs4820242, rs2284015, and rs2284017) in the CACNG2 gene is related to enhanced risk of PMP [57] (Table 1). It is well known that catecholamines influence pain perception [58], and polymorphisms of genes for these substances have been associated with PMP. ...
After breast surgery, women frequently develop chronic post-mastectomy pain (PMP). PMP refers to the occurrence of pain in and around the area of the mastectomy lasting beyond three months after surgery. The nature of factors leading to PMP is not well known. When PMP is refractory to analgesic treatment, it negatively impacts the lives of patients, increasing emotional stress and disability. For this reason, optimizing the quality of life of patients treated for this pathology has gained more importance. On the basis of the findings and opinions above, we present an overview of risk factors and predictors to be used as potential biomarkers in the personalized management of individual PMP. For this overview, we discuss scientific articles published in peer-reviewed journals written in the English language describing risk factors, predictors, and potential biomarkers associated with chronic pain after breast surgery. Our overview confirms that the identification of women at risk for PMP is fundamental to setting up the best treatment to prevent this outcome. Clinical practice can be planned through the interpretation of genotyping data, choosing drugs, and tailoring doses for each patient with the aim to provide safer and more effective individual analgesic treatment.
... There is, however, no clear consensus about the definition of "high risk patients" for CPBS, thus making it difficult to identify those subjects who might benefit the most from careful, early pain assessment. A complex multidisciplinary, multiparametric approach involving also psychosocial and genetic factors has been suggested to perioperatively stratify patients and identify those at high risk of developing CPBS (Bortsov et al. 2020;James 2017). Nevertheless, because genotyping is expensive and usually unfeasible in routine clinical practice, strategies for risk stratification are currently based on the evaluation of those clinical and anamnestic, pre-and intraoperative predictors of CPBS that have already been identified in the literature. ...
Background
Chronic pain after breast surgery (CPBS) has a disabling impact on postoperative health status. Mainly because of the lack of a clear definition, inconsistency does exist in the literature concerning both the actual incidence and the risk factors associated to CPBS. The aim of this prospective, observational study is to describe the incidence of and risk factors for CPBS, according to the definition provided by the IASP taskforce. The impact of CPBS on patients’ function and quality of life is also described.
Methods
Women aged 18+ undergoing oncological or reconstructive breast surgery from Jan until Apr 2018 at the Breast Unit of Careggi Hospital (Florence, Italy) were prospectively observed. Postoperative pain was measured at 0 h, 3 h, 6 h, 12 h, 24 h, 48 h, and 3 months (CPBS) after surgery. Preoperative, intraoperative, and postoperative factors were compared in CPBS and No-CPBS groups through multivariate logistic regression analysis.
Results
Among the 307 patients considered in this study, the incidence of CPBS was 28% [95% CI 23.1–33.4%]. Results from the logistic regression analysis suggest that axillary surgery (OR [95% CI], 2.99 [1.13–7.87], p = 0.03), preoperative use of pain medications (OR [95% CI], 2.04 [1.20–3.46], p = 0.01), and higher dynamic NRS values at 6 h postoperatively (OR [95% CI], 1.28 [1.05–1.55], p = 0.01) were all independent predictors for CPBS.
Conclusions
Chronic pain after breast surgery is a frequent complication. In our cohort, long-term use of analgesics for pre-existing chronic pain, axillary surgery, and higher dynamic NRS values at 6 h postoperatively were all factors associated with increased risk of developing CPBS. The possibility to early detect persistent pain, particularly in those patients at high risk for CPBS, might help physicians to more effectively prevent pain chronicisation.
Trial registration
ClinicalTrials.gov registration NCT04309929 .
... There is, however, no clear consensus about the de nition of "high risk patients" for CPBS, thus making it di cult to identify those subjects who might bene t the most from careful, early pain assessment. A complex multidisciplinary, multiparametric approach involving also psychosocial and genetic factors has been suggested to perioperatively stratify patients and identify those at high risk of developing CPBS (Bortsov et al. 2020;James 2017). Nevertheless, because genotyping is expensive and usually unfeasible in routine clinical practice, strategies for risk strati cation are currently based on the evaluation of those clinical and anamnestic, pre-and intraoperative predictors of CPBS that have already been identi ed in the literature. ...
Background. Chronic pain after breast surgery (CPBS) has a disabling impact on postoperative health status. Mainly because of the lack of a clear definition, inconsistency does exist in the literature concerning both the actual incidence and the risk factors associated to CPBS. The aim of this prospective, observational study is to describe the incidence of and risk factors for CPBS, according to the definition provided by the IASP taskforce. The impact of CPBS on patients’ function and quality of life is also described.
Methods. Women aged 18+ undergoing oncological or reconstructive breast surgery from Jan until Apr 2018 at the Breast Unit of Careggi Hospital (Florence, Italy) were prospectively observed. Postoperative pain was measured at 0hrs, 3hrs, 6hrs, 12hrs, 24hrs, 48hrs, and 3 months (CPBS) after surgery. Preoperative, intraoperative, and postoperative factors were compared in CPBS and No-CPBS groups through multivariate logistic regression analysis.
Results. Among the 307 patients considered in this study, the incidence of CPBS was 28% [95%CI 23.1%-33.4%]. Results from the logistic regression analysis suggest that axillary surgery (OR [95%CI], 2.99 [1.13-7.87], p=0.03), preoperative use of pain medications (OR [95%CI], 2.04 [1.20-3.46], p=0.01), and higher dynamic NRS values at 6 hours postoperatively (OR [95%CI], 1.28 [1.05-1.55], p=0.01) were all independent predictors for CPBS.
Conclusions. Chronic pain after breast surgery is a frequent complication. In our cohort, long-term use of analgesics for pre-existing chronic pain, axillary surgery, and higher dynamic NRS values at 6 hours postoperatively were all factors associated with increased risk of developing CPBS. The possibility to early detect persistent pain, particularly in those patients at high risk for CPBS, might help physicians to more effectively prevent pain chronicisation.
Trial registration: clinicalTrials.gov registration NCT04309929
... There is, however, no clear consensus about the de nition of "high risk patients" for CPBS, thus making it di cult to identify those subjects who might bene t the most from careful, early pain assessment. A complex multidisciplinary, multiparametric approach involving also psychosocial and genetic factors has been suggested to perioperatively stratify patients and identify those at high risk of developing CPBS (Bortsov et al. 2020;James 2017). Nevertheless, because genotyping is expensive and usually unfeasible in routine clinical practice, strategies for risk strati cation are currently based on the evaluation of those clinical and anamnestic, pre-and intraoperative predictors of CPBS that have already been identi ed in the literature. ...
Background. Chronic pain after breast surgery (CPBS) has a disabling impact on postoperative health status. Mainly because of the lack of a clear definition, inconsistency does exist in the literature concerning both the actual incidence and the risk factors associated to CPBS. The aim of this prospective, observational study is to describe the incidence of and risk factors for CPBS, according to the definition provided by the IASP taskforce. The impact of CPBS on patients’ function and quality of life is also described.
Methods. Adult female patients scheduled for oncological or reconstructive breast surgery at the Breast Unit of Careggi Hospital (Florence, Italy) were prospectively observed. Postoperative pain was evaluated at 3 months (CPBS) after surgery. Preoperative, intraoperative, and postoperative factors were compared in CPBS and No-CPBS groups through multivariate logistic regression analysis.
Results. Among the 307 patients considered in this study, the incidence of CPBS was 28% [95%CI 23.1%-33.4%]. Results from the logistic regression analysis suggest that axillary surgery (OR [95%CI], 2.99 [1.13-7.87], p=0.03), preoperative use of pain medications (OR [95%CI], 2.04 [1.20-3.46], p=0.01), and higher dynamic NRS values at 6 hours postoperatively (OR [95%CI], 1.28 [1.05-1.55], p=0.01) were all independent predictors for CPBS.
Conclusions. Chronic pain after breast surgery is a frequent complication. In our cohort, long-term use of analgesics for preexisting chronic pain, axillary surgery, and higher dynamic NRS values at 6 hours postoperatively were all factors associated with increased risk of developing CPBS. The possibility to early detect persistent pain, particularly in those patients at high risk for CPBS, might help physicians to more effectively prevent pain chronicisation.
Trial registration: clinicalTrials.gov registration NCT04309929
... The evaluation of the clinical characteristics of these patients may help to identify risk factors for the development of chronic NP after surgery, such as pre-and postoperative pain intensity or genetic susceptibility. 40 We acknowledge several limitations of the study. First, the study population was small. ...
Background
Primary retroperitoneal sarcoma (RPS) may require multivisceral resection (MVR). Clinical outcome (morbidity and renal function) and quality of life (QoL) are not as well reported as the oncologic outcome.Methods
Patients with primary RPS who underwent surgery between 2014 and 2016 were prospectively enrolled in an observational longitudinal study. At baseline, then at 4 and 12 months, the study measured Clavien–Dindo morbidity, estimated glomerular filtration rate (EGFR), EORTC QLQ-C30, QLQ-CR29, DN4 (neuropathic pain [NP]), lower-extremity functional scale (LEFS), and the brief pain inventory. The primary end point was the difference in global health status (GHS/QoL). The secondary end points were EGFR changes, difference in other QLQ-C30 scales, pain intensity, NP, and LEFS. The study is registered at ClinTrials.gov (NCT03480399).ResultsOf 74 patients, 58 were evaluable. Morbidity grade 3 or higher was 24.1%, and mortality was 1.3%. After nephrectomy, the mean 1-year EGFR change was −33.9%. The GHS/QoL at baseline was 58.6 and had increased of 6.9 points at 1 year, comparable with that of the general population. A transient worsening in pain and diarrhea had recovered at 12 months. Average pain was mild and did not differ at 12 months. However, NP was found in 41.4% of the patients and was significantly associated with resection of the psoas muscle. At baseline, LEFS was already lower than the normative value, and worsening after surgery was not clinically relevant.ConclusionA QoL measure after MVR in primary RPS is complex and requires multiple tools. Whereas overall MVR is safe and associated with an improvement in GHS/QoL, chronic NP is frequent and deserves specific attention. Pre-surgery rehabilitation tracks may help to prevent or reduce chronic NP.
... This finding can be used to attenuate the possibility of a major risk of developing chronic pain in certain patients. [95] ...
Background:
Pain is a common symptom in oncologic patients and its management is generally guided by pain individually perceived by patients and expressed through self-reported scales. However, the utility of these tools is limited because strongly dependent on patients' opinions. For this reason, more objective instruments are desirable.
Objective:
In this overview scientific articles indicating potential markers to be used for pain management in cancer were collected and discussed.
Methods:
research was performed on principal electronic scientific databases by using the words "pain", "cancer", "markers" as "biomarkers" as the main keywords, and findings describing potential biomarkers for the management of cancer pain were reported.
Results:
Studies on pain markers not specific for cancer typology (inflammatory, genetic, markers predicting response to analgesic drugs, neuroimaging markers) and pain markers for specific types of cancer (bone cancer, breast cancer, lung cancer, head and neck cancer, prostate cancer, cancer in pediatrics) are presented and commented.
Conclusion:
This overview supports the view of the involvement of inflammatory mediators in the mechanisms underlying cancer pain. Up today only a few data from research on markers can help in the management of pain, except for pro-inflammatory cytokines and other inflammatory indexes such as C-reactive protein (CRP). However, biomarkers are a promising strategy useful to predict pain intensity and to purchase objective quantification of analgesic response in guiding decisions on individual-tailored treatments in cancer patients.
... There is, however, no clear consensus about the de nition of "high risk patients" for CPBS, thus making it di cult to identify those subjects who might bene t the most from careful, early pain assessment. A complex multidisciplinary, multiparametric approach involving also psychosocial and genetic factors has been suggested to perioperatively stratify patients and identify those at high risk of developing CPBS (Bortsov et al. 2020;James 2017). Nevertheless, because genotyping is expensive and usually unfeasible in routine clinical practice, strategies for risk strati cation are currently based on the evaluation of those clinical and anamnestic, pre-and intraoperative predictors of CPBS that have already been identi ed in the literature. ...
Background. Chronic pain after breast surgery (CPBS) has a disabling impact on postoperative health status. Mainly because of the lack of a clear definition, inconsistency does exist in the literature concerning both the actual incidence and the risk factors associated to CPBS. The aim of this prospective, observational study is to describe the incidence of and risk factors for CPBS, according to the definition provided by the IASP taskforce. The impact of CPBS on patients’ function and quality of life is also described.
Methods. Adult female patients scheduled for oncological or reconstructive breast surgery at the Breast Unit of Careggi Hospital (Florence, Italy) were prospectively observed. Postoperative pain was evaluated at 2 months (“pain becoming chronic”) and at 3 months (CPBS) after surgery. Preoperative, intraoperative, and postoperative factors were compared in CPBS and No-CPBS groups through multivariate logistic regression analysis.
Results. Among the 307 patients considered in this study, the incidence of “pain becoming chronic” was 25.4% [95%CI 20.6%-30.7%], while that of CPBS was 28% [95%CI 23.1%-33.4%]. The presence of pain at 2 months concords with the presence of CPBS at 3 months (Cohen k coefficient 0.63, IC95% 0.54-0.73). Results from the logistic regression analysis suggest that axillary surgery (OR [95%CI], 2.99 [1.13-7.87], p=0.03), preoperative use of pain medications (OR [95%CI], 2.04 [1.20-3.46], p=0.01), and higher dynamic NRS values at 6 hours postoperatively (OR [95%CI], 1.28 [1.05-1.55], p=0.01) were all independent predictors for CPBS.
Conclusions. Chronic pain after breast surgery is a frequent complication. The presence of early pain at 2 months after surgery concords with the occurrence of CPBS. The possibility to early detect persistent pain, particularly in those patients at high risk for CPBS, might help physicians to more effectively prevent pain chronicization. In our cohort, long-term use of analgesics for preexisting chronic pain, axillary surgery, and higher dynamic NRS values at 6 hours postoperatively were all factors associated with increased risk of developing CPBS.
Trial registration: clinicalTrials.gov registration NCT04309929
... Many of the selected genes have been found to be associated with neurological diseases, including autism [SHANK2 (Monteiro and Feng, 2017;Won et al., 2012)], chronic pain [CACNG2 (Bortsov et al., 2019;Nissenbaum et al., 2010)], epilepsy [CHRNB2 (Diaz-Otero et al., 2008)], Huntington's disease [GRIN3A (Marco et al., 2013)], and neurodegenerative diseases [SYBU (Bereczki et al., 2018) Table S1). However, only a few genes have been studied in gliomas. ...
Gliomas are the most common primary brain cancers. In recent years, IDH mutation and 1p/19q codeletion have been suggested as biomarkers for the diagnosis, treatment, and prognosis of gliomas. However, these biomarkers are only effective for a part of glioma patients, and thus more biomarkers are still emergently needed. Recently, an electrochemical communication between normal neurons and glioma cells by neuro-glioma synapse has been reported. Moreover, it was discovered that breast-to-brain metastasis tumor cells have pseudo synapses with neurons, and these synapses were indicated to promote tumor progression and metastasis. Based on the above observations, we first curated a panel of 17 synapse-related genes and then proposed a metric, synapse score to quantify the “stemness” for each sample of 12 glioma gene expression datasets from TCGA, CGGA, and GEO. Strikingly, synapse score showed excellent predictive ability for the prognosis, diagnosis, and grading of gliomas. Moreover, being compared with the two established biomarkers, IDH mutation and 1p/19q codeletion, synapse score demonstrated independent and better predictive performance. In conclusion, this study proposed a quantitative method, synapse score, as an efficient biomarker for monitoring gliomas.
... Individual sensitivity for pain is considered to be determined by genetic background. Several genes have been linked to pain sensitivity [16,17]. ...
Background
This study discussed potential influences of UDP glucuronosyltransferase family 2 member B7 (UGT2B7) rs7439366 and rs12233719 polymorphisms on fentanyl sensitivity among Chinese gynecologic patients.
Material/Methods
UGT2B7 polymorphisms were genotyped by polymerase chain reaction (PCR) and direct sequencing. Before surgery, baseline latency to pain perception (PPLpre) and pain perception latency of the dominant hand (PPLpost) at 3 minutes after injecting fentanyl were measured by cold pressor-induced pain test. Perioperative fentanyl adoption referred to the total of fentanyl administration during and after operation. Intensity of spontaneous pain was appraised adopting 100-mm visual analog scale (VAS). Factorial analysis was performed by Mann-Whitney U test and Kruskal-Wallis H test.
Results
Significant differences of PPLpost (CC/CT/TT, P=0.038) and preoperative analgesic effect (CC/CT/TT, P=0.028) were discovered between the rs7439366 genotypes. PPLpost was significantly different between the CT and TT groups (P=0.009) and the CC+CT and TT groups (P=0.026). Preoperative analgesic effect was significantly different between the CT and TT groups (P=0.007) and the CC+CT and TT groups (P=0.009). All of the clinical features studied had no close association with rs12233719 SNP.
Conclusions
Gynecologic patients with rs7439366 TT genotype had significantly lower fentanyl sensitivity than the other 2 genotype carriers.
... doi: bioRxiv preprint first posted online Aug. 6, 2019; inflammatory pain (Sullivan et al., 2017;Tao et al., 2006). Its polymorphisms have been associated with chronic pain after mastectomy as well (Bortsov et al., 2019), although its role in itch transmission is not yet clear. Ttyh2 (Drosophila tweety homolog 2), a calcium-activated chloride channel (Suzuki, 2006), is highly enriched in MrgprA3 + neurons ( Figure 3C). ...
Itch, initiated by the activation of sensory neurons, is frequently associated with dermatological or systemic diseases and significantly affects patient quality of life. MrgprA3 ⁺ sensory neurons have been identified as one of the major itch-sensing neuronal populations. Mounting evidence has demonstrated that peripheral pathological conditions induce physiological regulations of sensory neurons, which is critical for the maintenance of chronic itch sensation. However, the underlying molecular mechanisms are not clear. Here we performed RNA sequencing of genetically labeled MrgprA3 ⁺ neurons under both naïve and allergic contact dermatitis condition. Our results revealed the unique molecular signature of itch-sensing neurons and the distinct transcriptional profile changes that result in response to dermatitis. We found enrichment of nine Mrgpr family members and two histamine receptors in MrgprA3 ⁺ neurons, suggesting that MrgprA3 ⁺ neurons are the main, direct neuronal target for histamine and Mrgprs agonists. In addition, Ptpn6 and Pcdh12 were identified as novel and highly selective markers of MrgprA3 ⁺ neurons. We also discovered that MrgprA3 ⁺ neurons respond to skin dermatitis in a way that is unique from other sensory neurons by regulating a combination of transcriptional factors, ion channels, and key molecules involved in synaptic transmission. These results significantly increase our knowledge of itch transmission and uncover potentially novel targets for combating itch.
Background
Persistent post-mastectomy pain (PPMP) is a significant negative outcome occurring after breast surgery, and understanding which individual women are most at risk is essential to targeting of preventive efforts. The biopsychosocial model of pain suggests that factors from many domains may importantly modulate pain processing and predict the progression to pain persistence.Methods
This prospective longitudinal observational cohort study used detailed and comprehensive psychosocial and psychophysical assessment to characterize individual pain-processing phenotypes in 259 women preoperatively. Pain severity and functional impact then were longitudinally assessed using both validated surgery-specific and general pain questionnaires to survey patients who underwent lumpectomy, mastectomy, or mastectomy with reconstruction in the first postsurgical year. An agnostic, multivariable modeling strategy identified consistent predictors of several pain outcomes at 12 months.ResultsThe preoperative characteristics most consistently associated with PPMP outcomes were preexisting surgical area pain, less education, increased somatization, and baseline sleep disturbance, with axillary dissection emerging as the only consistent surgical variable to predict worse pain. Greater pain catastrophizing, negative affect, younger age, higher body mass index (BMI), and chemotherapy also were independently predictive of pain impact, but not severity. Sensory disturbance in the surgical area was predicted by a slightly different subset of factors, including higher preoperative temporal summation of pain.Conclusions
This comprehensive approach assessing consistent predictors of pain severity, functional impact, and sensory disturbance may inform personalized prevention of PPMP and also may allow stratification and enrichment in future preventive studies of women at higher risk of this outcome, including pharmacologic and behavioral interventions and regional anesthesia.
Objective:
To review the current knowledge on the association of genetic variants with cancer pain.
Data sources:
Data-based publications and review articles retrieved from PubMed, CINAHL, and Web of Science, as well as an additional search in Google Scholar.
Conclusion:
Genetic variability can influence differential pain perception and response to opioids in cancer patients, which will have implications in the optimal personalized treatment of cancer pain. More studies are warranted to replicate findings.
Implications for nursing practice:
Nurses are poised to educate patients on biomarker testing and interpretation and to use precision pain management strategies based on this information.
In the brain, transmembrane AMPAR regulatory proteins (TARPs) critically influence the distribution, gating, and pharmacology of AMPARs, but the contribution of these auxiliary subunits to AMPAR-mediated signaling in the spinal cord remains unclear. We found that the Type I TARP γ-2 (stargazin) is present in lamina II of the superficial dorsal horn, an area involved in nociception. Consistent with the notion that γ-2 is associated with surface AMPARs, CNQX, a partial agonist at AMPARs associated with Type I TARPs, evoked whole-cell currents in lamina II neurons, but such currents were severely attenuated in γ-2-lacking stargazer (stg/stg) mice. Examination of EPSCs revealed the targeting of γ-2 to be synapse-specific; the amplitude of spontaneously occurring miniature EPSCs (mEPSCs) was reduced in neurons from stg/stg mice, but the amplitude of capsaicin-induced mEPSCs from C-fiber synapses was unaltered. This suggests that γ-2 is associated with AMPARs at synapses in lamina II but excluded from those at C-fiber inputs, a view supported by our immune histochemical colabeling data. Following induction of peripheral inflammation, a model of hyperalgesia, there was a switch in the current-voltage relationships of capsaicin-induced mEPSCs, from linear to inwardly rectifying, indicating an increased prevalence of calcium-permeable (CP) AMPARs. This effect was abolished in stg/stg mice. Our results establish that, although γ-2 is not typically associated with calcium-impermeable AMPARs at C-fiber synapses, it is required for the translocation of CP-AMPARs to these synapses following peripheral inflammation.
Patients with neuropathic pain are heterogeneous in etiology, pathophysiology, and clinical appearance. They exhibit a variety of pain-related sensory symptoms and signs (sensory profile). Different sensory profiles might indicate different classes of neurobiological mechanisms, and hence subgroups with different sensory profiles might respond differently to treatment. The aim of the investigation was to identify subgroups in a large sample of patients with neuropathic pain using hypothesis-free statistical methods on the database of 3 large multinational research networks (German Research Network on Neuropathic Pain (DFNS), IMI-Europain, and Neuropain). Standardized quantitative sensory testing was used in 902 (test cohort) and 233 (validation cohort) patients with peripheral neuropathic pain of different etiologies. For subgrouping, we performed a cluster analysis using 13 quantitative sensory testing parameters. Three distinct subgroups with characteristic sensory profiles were identified and replicated. Cluster 1 (sensory loss, 42%) showed a loss of small and large fiber function in combination with paradoxical heat sensations. Cluster 2 (thermal hyperalgesia, 33%) was characterized by preserved sensory functions in combination with heat and cold hyperalgesia and mild dynamic mechanical allodynia. Cluster 3 (mechanical hyperalgesia, 24%) was characterized by a loss of small fiber function in combination with pinprick hyperalgesia and dynamic mechanical allodynia. All clusters occurred across etiologies but frequencies differed. We present a new approach of subgrouping patients with peripheral neuropathic pain of different etiologies according to intrinsic sensory profiles. These 3 profiles may be related to pathophysiological mechanisms and may be useful in clinical trial design to enrich the study population for treatment responders.
In EBioMedicine Meng et al. (2015a) reported the results from their second genome-wide association study on neuropathic pain that aimed to identify novel genetic factors contributing to neuropathic pain in diabetic patients. The first study (Meng et al., 2015b) published earlier this year in the European Journal of Pain identified a cluster in the Chr8p21.3, next to GFRA2 gene locus, associated with cases of neuropathic pain defined as diabetic patients with a prescription history of at least one of five drugs specifically indicated for the treatment of neuropathic pain and in whom monofilament test result was positive for sensory neuropathy in at least one foot. The narrow-sense heritability of this phenotype was 11.00%. That study confirmed that diabetic neuropathic pain is a genetically controlled trait. In the second study in a larger sample the authors found sex-specific loci for men (a cluster in the Chr1p35.1; TLR12P-ZSCAN20) and women (a cluster in the Chr8p23.1, next to HMGB1P46) associated with the same phenotype, and men had higher narrow-sense heritability than women (28.5% vs. 16.7%, respectively) (Meng et al., 2015a). This is the first evidence for the sex-specific contribution of genetic factors to diabetic neuropathic pain.
Objective:
The underlying cause for postmastectomy pain syndrome (PMPS) and its impact on quality of life remain unclear. The objective of this study aims to determine retrospectively the prevalence of PMPS, its predicting risk factors, and its impact on quality of life.
Method:
In this survey, 225 women completed a battery of questionnaires. The questionnaires comprised the short form of the McGill Pain Questionnaire (SF-MPQ) exploring the characteristics and the description of the pain, and a Short Form-36 (SF-36) Health Survey evaluating quality of life. Logistic regression analyses were subsequently performed to identify risk factors for PMPS.
Results:
62 women (27.6%) reported PMPS as a consequence of surgery, and the pain was generally mild, mostly localized in breast area and intermittent. The pain was mainly described as aching (62.9%). 144 women reported sensory disturbance. We found that only the younger age is the predictive factor for PMPS (P < 0.05). Compared to the patients who did not experience PMPS, those who suffered from PMPS had significantly worse scores in role limitations due to physical problems (role physical, RP), body pain (BP), general health (GH), vitality (VT), role limitations due to emotional problems (role emotional, RE), and mental health (MH) (P < 0.05).
Conclusion:
PMPS is a significant problem, and the possible risk factors should be further explored. Patients with PMPS have significant worse quality of life, suggesting that patients should be well informed about the likelihood of experiencing the pain, and they may be afforded greater predictability and higher perceived control to enhance their quality of life.
Earlier studies have shown that the single nucleotide polymorphism (SNP) A118G (rs1799971) in the opioid receptor mu 1 (OPRM1) gene may affect pain sensitivity. In the present study we investigated whether the A118G SNP could predict clinical outcome regarding progression of pain intensity and disability in patients with low back pain and sciatica after lumbar disc herniation. Patients (n = 258) with lumbar disc herniation and sciatic pain, all European-Caucasian, were recruited from two hospitals in Norway. Pain and disability were rated on a visual analog scale (VAS), by McGill Sensory Questionnaire and by Oswestry Disability Index (ODI) over a 12 months period. The data revealed a significant interaction between sex and A118G genotype regarding the pain intensity during the 12 months (VAS, p = 0.002; McGill, p = 0.021; ODI, p = 0.205, repeated-measures ANOVA). We found that */G women had a slower recovery rate than the */G men. Actually, the */G women had 2.3 times as much pain as the */G men 12 months after the disc herniation (VAS, p = 0.043, one-way ANOVA; p = 0.035, Tukey HSD). In contrast, the A/A women and A/A men seemed to have almost exactly the same recovery rate. The present data suggest that OPRM1 G allele increases the pain intensity in women, but has a protective effect in men the first year after disc herniation.
Pain sensitivity varies substantially among humans. A significant part of the human population develops chronic pain conditions that are characterized by heightened pain sensitivity. We identified three genetic variants (haplotypes) of the gene encoding catecholamine-O-methyltransferase (COMT) that we designated as low pain sensitivity (LPS), average pain sensitivity (APS) and high pain sensitivity (HPS). We show that these haplotypes encompass 96% of the human population, and five combinations of these haplotypes are strongly associated (P=0.0004) with variation in the sensitivity to experimental pain. The presence of even a single LPS haplotype diminishes, by as much as 2.3 times, the risk of developing myogenous temporomandibular joint disorder (TMD), a common musculoskeletal pain condition. The LPS haplotype produces much higher levels of COMT enzymatic activity when compared with the APS or HPS haplotypes. Inhibition of COMT in the rat results in a profound increase in pain sensitivity. Thus, COMT activity substantially influences pain sensitivity, and the three major haplotypes determine COMT activity in humans that inversely correlates with pain sensitivity and the risk of developing TMD.
Chronic neuropathic pain is affected by specifics of the precipitating neural pathology, psychosocial factors, and by genetic predisposition. Little is known about the identity of predisposing genes. Using an integrative approach, we discovered that CACNG2 significantly affects susceptibility to chronic pain following nerve injury. CACNG2 encodes for stargazin, a protein intimately involved in the trafficking of glutamatergic AMPA receptors. The protein might also be a Ca(2+) channel subunit. CACNG2 has previously been implicated in epilepsy. Initially, using two fine-mapping strategies in a mouse model (recombinant progeny testing [RPT] and recombinant inbred segregation test [RIST]), we mapped a pain-related quantitative trait locus (QTL) (Pain1) into a 4.2-Mb interval on chromosome 15. This interval includes 155 genes. Subsequently, bioinformatics and whole-genome microarray expression analysis were used to narrow the list of candidates and ultimately to pinpoint Cacng2 as a likely candidate. Analysis of stargazer mice, a Cacng2 hypomorphic mutant, provided electrophysiological and behavioral evidence for the gene's functional role in pain processing. Finally, we showed that human CACNG2 polymorphisms are associated with chronic pain in a cohort of cancer patients who underwent breast surgery. Our findings provide novel information on the genetic basis of neuropathic pain and new insights into pain physiology that may ultimately enable better treatments.
Stargazer mice are characterized by ataxia and seizures, which resemble the human disorder absence epilepsy. Stargazin, the protein mutated in stargazer mice, promotes the expression and function of neuronal AMPA receptors (AMPARs). However, it is unclear how decreased expression of excitatory AMPARs generates stargazer seizures, given that seizures often result from increased neuronal excitability. Additionally, although stargazer ataxia has been attributed to loss of AMPARs from cerebellar granule cells, other cerebellar neurons have not been examined. To examine the role of AMPAR dysfunction in these behavioral phenotypes, electrophysiological recordings were used to probe AMPAR regulation in relevant brain regions. We found that both cerebellar Purkinje cells and inhibitory thalamic reticular nucleus neurons have strongly reduced synaptic AMPAR function in stargazer mice. Together, our data suggest that impaired AMPAR regulation in multiple neuron populations may contribute to the behavioral phenotypes of absence seizures and ataxia seen in stargazer mice and imply that an understanding of human genetic disorders will require knowledge of both the genes that are mutated as well as their precise cellular expression pattern.
The prevalence of the postmastectomy pain syndrome (PMPS) and its clinical characteristics was assessed in a group of patients who had undergone surgery for breast cancer at the Department of Surgery, Odense University Hospital, within the period of 1 May 2003 to 30 April 2004. The study included 258 patients and a reference group of 774 women. A questionnaire was mailed to the patients 1 1/2 year after surgery and to the women in the reference group. The PMPS was defined as pain located in the area of the surgery or ipsilateral arm, present at least 4 days per week and with an average intensity of at least 3 on a numeric rating scale from 0 to 10. The prevalence of PMPS was found to be 23.9%. The odds ratio of developing PMPS was 2.88 (95% confidence interval 1.84-4.51). Significant risk factors were as follows: having undergone breast surgery earlier (OR 8.12), tumour located in the upper lateral quarter (OR 6.48) and young age (OR 1.04). This study shows that, although recent advances in the diagnostic and surgical procedures have reduced the frequency of the more invasive surgical procedures, there still is a considerable risk of developing PMPS after treatment of breast cancer.
A novel gene (Cacng2;γ2
) encoding a protein similar to the voltage-activated Ca2+ channel γ1 subunit was identified as the defective gene in the epileptic and ataxic mouse, stargazer. In this study, we analyzed the
association of this novel neuronal γ2 subunit with Ca2+ channels of rabbit brain, and the function of the γ2 subunit in recombinant neuronal Ca2+ channels expressed inXenopus oocytes. Our results showed that the γ2 subunit and a closely related protein (called γ3) co-sedimented and co-immunoprecipitated with neuronal Ca2+ channel subunits in vivo. Electrophysiological analyses showed that γ2co-expression caused a significant decrease in the current amplitude of both α1B(α12.2)-class (36.8%) and α1A(α12.1)-class (39.7%) Ca2+channels (α1β3α2δ). Interestingly, the inhibitory effects of the γ2 subunit on current amplitude were dependent on the co-expression of the α2δ subunit. In addition, co-expression of γ2 or γ1 also significantly decelerates the activation kinetics of α1B-class Ca2+channels. Taken together, these results suggest that the γ2 subunit is an important constituent of the neuronal Ca2+ channel complex and that it down-regulates neuronal Ca2+ channel activity. Furthermore, the γ2 subunit likely contributes to the fine-tuning of neuronal Ca2+ channels by counterbalancing the effects of the α2δ subunit.
Stargazin (gamma2) and the closely related gamma3, and gamma4 transmembrane proteins are part of a family of proteins that may act as both neuronal voltage-dependent calcium channel (VDCC) gamma subunits and transmembrane alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproponinc (AMPA) receptor regulatory proteins (TARPs). In this investigation, we examined the distribution patterns of the stargazin-like proteins gamma2, gamma3, and gamma4 in the human central nervous system (CNS). In addition, we investigated whether human gamma2 or gamma4 could modulate the electrophysiological properties of a neuronal VDCC complex transiently expressed in Xenopus oocytes.
The mRNA encoding human gamma2 is highly expressed in cerebellum, cerebral cortex, hippocampus and thalamus, whereas gamma3 is abundant in cerebral cortex and amygdala and gamma4 in the basal ganglia. Immunohistochemical analysis of the cerebellum determined that both gamma2 and gamma4 are present in the molecular layer, particularly in Purkinje cell bodies and dendrites, but have an inverse expression pattern to one another in the dentate cerebellar nucleus. They are also detected in the interneurons of the granule cell layer though only gamma2 is clearly detected in granule cells. The hippocampus stains for gamma2 and gamma4 throughout the layers of the every CA region and the dentate gyrus, whilst gamma3 appears to be localized particularly to the pyramidal and granule cell bodies. When co-expressed in Xenopus oocytes with a CaV2.1/beta4 VDCC complex, either in the absence or presence of an alpha2delta2 subunit, neither gamma2 nor gamma4 significantly modulated the VDCC peak current amplitude, voltage-dependence of activation or voltage-dependence of steady-state inactivation.
The human gamma2, gamma3 and gamma4 stargazin-like proteins are detected only in the CNS and display differential distributions among brain regions and several cell types in found in the cerebellum and hippocampus. These distribution patterns closely resemble those reported by other laboratories for the rodent orthologues of each protein. Whilst the fact that neither gamma2 nor gamma4 modulated the properties of a VDCC complex with which they could associate in vivo in Purkinje cells adds weight to the hypothesis that the principal role of these proteins is not as auxiliary subunits of VDCCs, it does not exclude the possibility that they play another role in VDCC function.
The quantity of neurotransmitter released into the synaptic cleft, the reliability with which it is released, and the response of the postsynaptic cell to that transmit- ter all contribute to the strength of a synaptic connection. The presynaptic nerve terminal is a major regulatory site for activity-dependent changes in synaptic func- tion. Ionotropic receptors for the inhibitory amino acid GABA, expressed on the presynaptic terminals of crustacean motor axons and vertebrate sensory neurons, were the first well-defined mechanism for the heterosynaptic transmitter-mediated regulation of transmitter release. Recently, presynaptic ionotropic receptors for a large range of transmitters have been found to be widespread throughout the central and peripheral nervous systems. In this review, we first consider some general theoretical issues regarding whether and how presynaptic ionotropic re- ceptors are important regulators of presynaptic function. We consider the criteria that should be met to identify a presynaptic ionotropic receptor and its regulatory function and review several examples of presynaptic receptors that meet at least some of those criteria. We summarize the classic studies of presynaptic inhibition mediated by GABA-gated Cl channels and then focus on presynaptic nicotinic ACh receptors and presynaptic glutamate receptors. Finally, we briefly discuss evidence for other types of presynaptic ionotropic receptors.
The AMPA-type glutamate receptors mediate the majority of the fast excitatory synaptic transmission and critically contribute to synaptic plasticity in the brain, hence the existence of numerous trafficking proteins dedicated to regulation of their synaptic delivery and turnover. Stargazin (also termed gamma2) is a member of a recently identified protein family termed transmembrane AMPA receptor regulatory proteins (TARPs). TARPs physically associate with AMPA receptors and participate in their surface delivery and anchoring at the postsynaptic membrane. Here, we report that next to its trafficking roles, stargazin may also act as a positive allosteric modulator of AMPA receptor ion channel function. Coexpression of stargazin with AMPA receptor subunits, either in Xenopus oocytes or in human embryonic kidney 293 cells, significantly reduced receptor desensitization in response to glutamate. Receptor deactivation rates were also slowed, and the recovery from desensitization was accelerated. Structurally, based on the data showing a tight correlation between desensitization and the stability of the AMPA receptor intradimer interface, we propose that binding of stargazin may stabilize the receptor conformation. Functionally, our data suggest that AMPA receptors complexed with stargazin (and possibly also with other TARPs) at the postsynaptic membrane are significantly more responsive to synaptically released glutamate compared with AMPA receptors lacking stargazin/TARP interaction. The putative existence of such two states of synaptic AMPA receptors, with and without stargazin/TARP binding, may provide a novel mechanism for regulation of excitatory synaptic strength during development and/or in synaptic plasticity in the adult brain.
Stargazer ( stg ) mutant mice fail to express stargazin [transmembrane AMPA receptor regulatory protein γ2 (TARPγ2)] and consequently experience absence seizure-like thalamocortical spike-wave discharges that pervade the hippocampal formation via the dentate gyrus (DG). As in other seizure models, the dentate granule cells of stg develop elaborate reentrant axon collaterals and transiently overexpress brain-derived neurotrophic factor. We investigated whether GABAergic parameters were affected by the stg mutation in this brain region. GABA A receptor (GABAR) α4 and β3 subunits were consistently upregulated, GABAR δ expression appeared to be variably reduced, whereas GABAR α1, β2, and γ2 subunits and the GABAR synaptic anchoring protein gephyrin were essentially unaffected. We established that the α4βγ2 subunit-containing, flunitrazepam-insensitive subtype of GABARs, not normally a significant GABAR in DG neurons, was strongly upregulated in stg DG, apparently arising at the expense of extrasynaptic α4βδ-containing receptors. This change was associated with a reduction in neurosteroid-sensitive GABAR-mediated tonic current. This switch in GABAR subtypes was not reciprocated in the tottering mouse model of absence epilepsy implicating a unique, intrinsic adaptation of GABAergic networks in stg .
Contrary to previous reports that suggested that TARPγ2 is expressed in the dentate, we find that TARPγ2 was neither detected in stg nor control DG. We report that TARPγ8 is the principal TARP isoform found in the DG and that its expression is compromised by the stargazer mutation. These effects on GABAergic parameters and TARPγ8 expression are likely to arise as a consequence of failed expression of TARPγ2 elsewhere in the brain, resulting in hyperexcitable inputs to the dentate.
Auxiliary gamma subunits are an important component of high-voltage-activated calcium (Ca(V)) channels, but their precise regulatory role remains to be determined. In the current report, we have used complementary approaches including molecular biology and electrophysiology to investigate the influence of the gamma subunits on neuronal Ca(V) channel activity and expression. We found that coexpression of gamma2 or gamma3 subunits drastically inhibited macroscopic currents through recombinant N-type channels (Ca(V)2.2/beta3/alpha2delta) in HEK-293 cells. Using inhibitors of internalization, we found that removal of functional channels from the plasma membrane is an improbable mechanism of current regulation by gamma. Instead, changes in current amplitude could be attributed to two distinct mechanisms. First, gamma subunit expression altered the voltage dependence of channel activity. Second, gamma subunit expression reduced N-type channel synthesis via activation of the endoplasmic reticulum unfolded protein response. Together, our findings (1) corroborate that neuronal gamma subunits significantly downregulate Ca(V)2.2 channel activity, (2) uncover a role for the gamma2 subunit in Ca(V)2.2 channel expression through early components of the biosynthetic pathway, and (3) suggest that, under certain conditions, channel protein misfolding could be induced by interactions with the gamma subunits, supporting the notion that Ca(V) channels constitute a class of difficult-to-fold proteins.
AMPA receptors mediate the majority of fast synaptic transmission and underlie several forms of synaptic plasticity. AMPARs also have an important role in several neuronal pathologies. Therefore, studying the structure and function of these receptors is important for understanding general mechanisms of synaptic transmission as well as for the development of new therapies. A recent study identified the apparent binding sites for GYKI 53655 (GYKI) and CP-465,022 (CP) at the interface between the glutamate binding core and the transmembrane domains. The emerging role of transmembrane AMPA receptor regulatory proteins (TARPs) in AMPAR function raises the possibility that the antagonism of these receptors is also affected by TARPs such as stargazin. Here we compare the antagonism of the competitive antagonist CNQX and the negative allosteric modulators GYKI, and CP in the absence and presence of stargazin. We found that stargazin decreases the apparent affinity of GluR1 for CNQX, which is most likely explained by a partial agonistic effect of CNQX. In contrast, stargazin increases the affinity for GYKI, and has only a small effect on CP binding. Because inhibition of recently described GYKI insensitive receptors is restored by co-expression with stargazin, our data suggest that the identified residues do not constitute the full GYKI binding site. We could show that the ectodomain of stargazin controls the change in agonist sensitivity. Mutations in the identified binding regions for GYKI and CP dramatically reduced surface expression. Our data provides further evidence that TARPs alter the conformation of pore-forming subunits and thereby affects antagonist interaction.
AMPA receptors (AMPARs) mediate the majority of fast excitatory transmission in the brain and critically contribute to synaptic plasticity and pathology. AMPAR trafficking and gating are tightly controlled by auxiliary transmembrane AMPAR regulatory proteins (TARPs). Here, using systematic domain swaps with the TARP-insensitive kainate receptor GluK2, we show that AMPAR interaction with the prototypical TARP stargazin/γ2 primarily involves the AMPAR membrane domains M1 and M4 of neighboring subunits, initiated or stabilized by the AMPAR C-tail, and that these interactions are sufficient to enable full receptor modulation. Moreover, employing TARP chimeras disclosed a key role in this process also for the TARP transmembrane domains TM3 and TM4 and extracellular loop 2. Mechanistically, our data support a two-step action in which binding of TARP to the AMPAR membrane domains destabilizes the channel closed state, thereby enabling an efficient opening upon agonist binding, which then stabilizes the open state via subsequent interactions.
Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths that will occur in the United States in the current year and compiles the most recent data on cancer incidence, mortality, and survival. Incidence data were collected by the Surveillance, Epidemiology, and End Results Program; the National Program of Cancer Registries; and the North American Association of Central Cancer Registries. Mortality data were collected by the National Center for Health Statistics. In 2017, 1,688,780 new cancer cases and 600,920 cancer deaths are projected to occur in the United States. For all sites combined, the cancer incidence rate is 20% higher in men than in women, while the cancer death rate is 40% higher. However, sex disparities vary by cancer type. For example, thyroid cancer incidence rates are 3-fold higher in women than in men (21 vs 7 per 100,000 population), despite equivalent death rates (0.5 per 100,000 population), largely reflecting sex differences in the "epidemic of diagnosis." Over the past decade of available data, the overall cancer incidence rate (2004-2013) was stable in women and declined by approximately 2% annually in men, while the cancer death rate (2005-2014) declined by about 1.5% annually in both men and women. From 1991 to 2014, the overall cancer death rate dropped 25%, translating to approximately 2,143,200 fewer cancer deaths than would have been expected if death rates had remained at their peak. Although the cancer death rate was 15% higher in blacks than in whites in 2014, increasing access to care as a result of the Patient Protection and Affordable Care Act may expedite the narrowing racial gap; from 2010 to 2015, the proportion of blacks who were uninsured halved, from 21% to 11%, as it did for Hispanics (31% to 16%). Gains in coverage for traditionally underserved Americans will facilitate the broader application of existing cancer control knowledge across every segment of the population. CA Cancer J Clin 2017. © 2017 American Cancer Society.
Pain is a quite frequent complaint accompanying numerous pathologies. Among these pathological cases numerous neuropathies are retrieved with identified etiologies (chemotherapies, diabetes, surgeries[horizontal ellipsis]) and also more diffuse syndromes such as fibromyalgia. More broadly, pain is one of the first consequences of the majority of inherited diseases. Despite its importance for the quality of life, current pain management is limited to drugs that are either old, or with a limited efficacy or that possess a bad benefit/risk ratio. As no new pharmacological concept has led to new analgesics in the last decades, the discovery of new medications is needed, and to this aim the identification of new druggable targets in pain transmission is a first step. Therefore studies of ion channels in pain pathways are extremely active. This is particularly true with ion channels in peripheral sensory neurons in Dorsal Root Ganglia (DRG) known now to express unique sets of these channels. Moreover, both spinal and supra spinal levels are clearly important in pain modulation. Among these ion channels, we and others revealed the important role of low voltage-gated calcium channels in cellular excitability in different steps of the pain pathways. These channels, by being activated nearby resting membrane potential have biophysical characteristics suited to facilitate action potential generation and rhythmicity. In this review we will present the current knowledge on the role of these channels in the perception and modulation of pain.
Persistent postoperative pain is a well-established clinical problem with potential severe personal and socioeconomic implications. The prevalence of persistent pain varies across surgery types. Severe persistent pain and related impairment occur in 5% to 10% of patients after groin hernia repair. The substantial interindividual variability in pain-related phenotypes within each surgery type cannot be explained by environmental factors alone, suggesting that genetic variation may play a role. We investigated the contribution of COMT and GCH1 to persistent postherniotomy pain (PPP)-related functional impairment. Prospective data from 429 Caucasian male patients with hernia were collected. Three COMT and 2 GCH1 tagging single-nucleotide polymorphisms (SNPs) were genotyped and analyzed for association with PPP-related activity impairment at 6 months after herniotomy. Fifty-five (12.8%) patients had moderate-to-severe pain-related activity impairment 6 months postoperatively as measured by Activity Assessment Scale (≥8.3). Patients with the G allele of COMT SNP rs6269 and C allele of COMT SNP rs4633 had less impairment (P = 0.03 and 0.01, respectively); in addition, the COMT haplotype GCG was associated with less impairment. For GCH1, the A allele of SNP rs3783641, T allele of rs8007267, and AT haplotype showed a protective effect trend (although nonsignificant; P = 0.08, 0.06, and 0.08, respectively). A prediction model of substantial PPP-related activity impairment, combining COMT and GCH1 SNPs with clinical, psychophysical, and psychological risk factors, had a "good" (0.8 < area under curve < 0.9) discriminatory power. These data suggest that functional variations in COMT and GCH1 combined with clinical factors are predictive of PPP-related impairment after groin herniotomy.
New drug treatments, clinical trials, and standards of quality for assessment of evidence justify an update of evidence-based recommendations for the pharmacological treatment of neuropathic pain. Using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE), we revised the Special Interest Group on Neuropathic Pain (NeuPSIG) recommendations for the pharmacotherapy of neuropathic pain based on the results of a systematic review and meta-analysis.
Between April, 2013, and January, 2014, NeuPSIG of the International Association for the Study of Pain did a systematic review and meta-analysis of randomised, double-blind studies of oral and topical pharmacotherapy for neuropathic pain, including studies published in peer-reviewed journals since January, 1966, and unpublished trials retrieved from ClinicalTrials.gov and websites of pharmaceutical companies. We used number needed to treat (NNT) for 50% pain relief as a primary measure and assessed publication bias; NNT was calculated with the fixed-effects Mantel-Haenszel method.
229 studies were included in the meta-analysis. Analysis of publication bias suggested a 10% overstatement of treatment effects. Studies published in peer-reviewed journals reported greater effects than did unpublished studies (r(2) 9·3%, p=0·009). Trial outcomes were generally modest: in particular, combined NNTs were 6·4 (95% CI 5·2-8·4) for serotonin-noradrenaline reuptake inhibitors, mainly including duloxetine (nine of 14 studies); 7·7 (6·5-9·4) for pregabalin; 7·2 (5·9-9·21) for gabapentin, including gabapentin extended release and enacarbil; and 10·6 (7·4-19·0) for capsaicin high-concentration patches. NNTs were lower for tricyclic antidepressants, strong opioids, tramadol, and botulinum toxin A, and undetermined for lidocaine patches. Based on GRADE, final quality of evidence was moderate or high for all treatments apart from lidocaine patches; tolerability and safety, and values and preferences were higher for topical drugs; and cost was lower for tricyclic antidepressants and tramadol. These findings permitted a strong recommendation for use and proposal as first-line treatment in neuropathic pain for tricyclic antidepressants, serotonin-noradrenaline reuptake inhibitors, pregabalin, and gabapentin; a weak recommendation for use and proposal as second line for lidocaine patches, capsaicin high-concentration patches, and tramadol; and a weak recommendation for use and proposal as third line for strong opioids and botulinum toxin A. Topical agents and botulinum toxin A are recommended for peripheral neuropathic pain only.
Our results support a revision of the NeuPSIG recommendations for the pharmacotherapy of neuropathic pain. Inadequate response to drug treatments constitutes a substantial unmet need in patients with neuropathic pain. Modest efficacy, large placebo responses, heterogeneous diagnostic criteria, and poor phenotypic profiling probably account for moderate trial outcomes and should be taken into account in future studies.
NeuPSIG of the International Association for the Study of Pain.
Copyright © 2015 Elsevier Ltd. All rights reserved.
Background
Moderate to severe pain in the first week after axillary lymph node dissection (ALND) for breast cancer is experienced by approximately 50% of the patients. Damage to the intercostobrachial nerve (ICBN) has been proposed as a risk factor for the development of persistent pain following breast cancer surgery but with limited information on acute post-operative pain. The aim of the present study was to examine the influence of ICBN handling on pain during the first week after ALND. Methods
The study was part of a larger prospective cohort study on persistent pain after breast cancer treatment. Pain and sensory disturbances were assessed pre-operatively, within the first 72h post-operatively and a week after surgery. Intraoperative handling of the nerve was recorded by the surgeon as preserved, partially preserved or sectioned. ResultsOne hundred forty-one patients were treated with ALND level I+II, and the ICBN could be identified in 125 (89%) patients. Of the 17 not identified, eight were stated as without any sign of the nerve and were included in analysis as sectioned. Thus, the analysis included 133 patients in which 45 (34%) of these the ICBN was preserved, 39 (29%) partially preserved and 49 (37%) sectioned. At 1 week after surgery, 104 patients (78%) reported pain, whereas 35 (26%) reported moderate to severe pain. There was no difference between the ICBN groups in pain scores or sensory disturbances measured pre-operatively compared to 1 week post-operatively. Conclusion
The type of ICBN handling during ALND may not influence acute post-operative pain in the first week after surgery.
Persistent pain following breast cancer treatments remains a significant clinical problem despite improved treatment strategies.1 Data on factors associated with persistent pain are needed to develop prevention and treatment strategies and to improve the quality of life for breast cancer patients. This prospective study examined the prevalence and severity of and the factors associated with chronic pain after breast cancer surgery and adjuvant treatments.
Background:
This article describes the methods and results of the early part (experimental pain tests and postoperative analgesia) of a study that assesses genetic and other factors related to acute pain and persistent pain after treatment of breast cancer in a prospective cohort of 1,000 women.
Methods:
One thousand consenting patients were recruited to the study. Before surgery (breast resection or mastectomy with axillary surgery), the patients filled in questionnaires about health, life style, depression (Beck Depression Inventory), and anxiety (State-Trait Anxiety Inventory). They were also exposed to experimental tests measuring heat (43° and 48°C, 5 s) and cold (2-4°C) pain intensity and tolerance. Anesthesia was standardized with propofol and remifentanil, and postoperative analgesia was optimized with i.v. oxycodone.
Results:
The patients showed significant interindividual variation in heat and cold pain sensitivity and cold pain tolerance. There was a strong correlation between the experimental pain measures across the tests. Presence of chronic pain, the number of previous operations, and particularly state anxiety were related to increased pain sensitivity. Previous smoking correlated with decreased heat pain sensitivity. These factors explained 4-5% of the total variance in pain sensitivity in these tests. Oxycodone consumption during 20 h was significantly higher in patients who had axillary clearance. Oxycodone consumption had only a weak correlation with the experimental pain measures.
Conclusions:
Contact heat and cold pressure tests identify variability in pain sensitivity which is modified by factors such as anxiety, chronic pain, previous surgery, and smoking. High levels of anxiety are connected to increased pain sensitivity in experimental and acute postoperative pain.
GTP cyclohydrolase (GCH1) is rate limiting for tetrahydrobiopterin (BH4) synthesis, where BH4 is a cofactor for nitric oxide (NO) synthases and aromatic hydroxylases. GCH1 polymorphisms are implicated in the pathophysiology of pain, but have not been investigated in African populations. We examined GCH1 and pain in sickle cell anemia where GCH1 rs8007267 was a risk factor for pain crises in discovery (n=228; Odds Ratio [OR] 2.26; P=0.009) and replication (n=513; OR 2.23; P=0.004) cohorts. In vitro, cells from sickle cell anemia subjects homozygous for the risk allele produced higher BH4. In vivo physiological studies of traits likely to be modulated by GCH1 showed rs8007267 is associated with altered endothelial dependent blood flow in females with SCA (8.42% of variation; P=0.002). The GCH1 pain association is attributable to an African haplotype with where its sickle cell anemia pain association is limited to females (OR 2.69; 95% CI 1.21-5.94; P=0.01) and has the opposite directional association described in Europeans independent of global admixture. The presence of a GCH1 haplotype with high BH4 in populations of African ancestry could explain the association of rs8007267 with sickle cell anemia pain crises. The vascular effects of GCH1 and BH4 may also have broader implications for cardiovascular disease in populations of African ancestry.
Persistent postmastectomy pain (PPMP) is increasingly recognized as a major individual and public health problem. Although previous studies have investigated surgical, medical, and demographic risk factors, in this study we aimed to more clearly elucidate the relationship of psychosocial factors to PPMP. Postmastectomy patients (611) were queried about pain location, severity, and burden 38.3 ± 35.4 months postoperatively. Validated questionnaires for depressive symptoms, anxiety, sleep, perceived stress, emotional stability, somatization, and catastrophizing were administered. Detailed surgical, medical, and treatment information was abstracted from patients' medical records. One third (32.5%) of patients reported PPMP, defined as ≥3/10 pain severity in the breast, axilla, side, or arm, which did not vary according to time since surgery. Multiple regression analysis revealed significant and independent associations between PPMP and psychosocial factors, including catastrophizing, somatization, anxiety, and sleep disturbance. Conversely, treatment-related factors including surgical type, axillary node dissection, surgical complication, recurrence, tumor size, radiation, and chemotherapy were not significantly associated with PPMP. These data confirm previous studies suggesting that PPMP is relatively common and provide new evidence of significant associations between psychosocial characteristics such as catastrophizing with PPMP, regardless of the surgical and medical treatment that patients receive, which may lead to novel strategies in PPMP prevention and treatment.
This cross-sectional cohort study of 611 postmastectomy patients investigated severity, location, and frequency of pain a mean of 3.2 years after surgery. Significant associations between pain severity and individual psychosocial attributes such as catastrophizing were found, whereas demographic, surgical, medical, and treatment-related factors were not associated with persistent pain.
The enzyme catechol-O-methyltransferase (COMT) metabolizes catecholamine neurotransmitters involved in a number of physiological functions, including pain perception. Both human and mouse COMT genes possess functional polymorphisms contributing to interindividual variability in pain phenotypes such as sensitivity to noxious stimuli, severity of clinical pain, and response to pain treatment. In this study, we found that the effects of Comt functional variation in mice are modality specific. Spontaneous inflammatory nociception and thermal nociception behaviors were correlated the most with the presence of the B2 SINE transposon insertion residing in the 3'UTR mRNA region. Similarly, in humans, COMT functional haplotypes were associated with thermal pain perception and with capsaicin-induced pain. Furthermore, COMT genetic variations contributed to pain behaviors in mice and pain ratings in humans in a sex-specific manner. The ancestral Comt variant, without a B2 SINE insertion, was more strongly associated with sensitivity to capsaicin in female vs male mice. In humans, the haplotype coding for low COMT activity increased capsaicin-induced pain perception in women, but not men. These findings reemphasize the fundamental contribution of COMT to pain processes, and provide a fine-grained resolution of this contribution at the genetic level that can be used to guide future studies in the area of pain genetics.
Chronic pain is a classic example of gene × environment interaction: inflammatory and/or nerve injuries are known or suspected to be the etiology of most chronic pain syndromes, but only a small minority of those subjected to such injuries actually develop chronic pain. Once chronic pain has developed, pain severity and analgesic response are also highly variable among individuals. Although animal genetics studies have been ongoing for over two decades, only recently have comprehensive human twin studies and large-scale association studies been performed. Here, I review recent and accelerating progress in, and continuing challenges to, the identification of genes contributing to such variability. Success in this endeavor will hopefully lead to both better management of pain using currently available therapies and the development and/or prioritizing of new ones.
Persistent postherniotomy pain (PPP) affects everyday activities in 5-10% of patients. Identification of predisposing factors may help to identify the risk groups and guide anesthetic or surgical procedures in reducing risk for PPP.
A prospective study was conducted in 464 patients undergoing open or laparoscopic transabdominal preperitoneal elective groin hernia repair. Primary outcome was identification of risk factors for substantial pain-related functional impairment at 6 months postoperatively assessed by the validated Activity Assessment Scale (AAS). Data on potential risk factors for PPP were collected preoperatively (pain from the groin hernia, preoperative AAS score, pain from other body regions, and psychometric assessment). Pain scores were collected on days 7 and 30 postoperatively. Sensory functions including pain response to tonic heat stimulation were assessed by quantitative sensory testing preoperatively and 6 months postoperatively to assess nerve damage.
Four hundred sixty-four patients were included, whereof 442 were examined at 6 months (95.3% follow-up). Fifty-five patients (12.4%) had "moderate/severe" PPP at 6 months. Logistic regression analysis identified four risk factors for PPP: preoperative AAS score, preoperative pain to tonic heat stimulation, 30-day postoperative pain intensity, and sensory dysfunction in the groin at 6 months (nerve damage) (all P < 0.03). A risk prediction model of only preoperative factors and choice of surgical technique revealed increased preoperative AAS score, increased preoperative pain to heat stimulation, and open surgery to increase the risk for PPP (all P < 0.02).
PPP is related to both patient and surgical factors. Patients with a high preoperative AAS score and high pain response to a standardized heat stimulus may preferably be treated using an operative technique with lowest risk for nerve damage.
Persistent pain and sensory disturbances following surgical treatment for breast cancer is a significant clinical problem. The pathogenic mechanisms are complex and may be related to patient characteristics, surgical technique, and adjuvant therapy.
To examine prevalence of and factors associated with persistent pain after surgical treatment for breast cancer.
A nationwide cross-sectional questionnaire study of 3754 women aged 18 to 70 years who received surgery and adjuvant therapy (if indicated) for primary breast cancer in Denmark between January 1, 2005, and December 31, 2006. A study questionnaire was sent to the women between January and April 2008.
Prevalence, location, and severity of persistent pain and sensory disturbances in 12 well-defined treatment groups assessed an average of 26 months after surgery, and adjusted odds ratio (OR) of reported pain and sensory disturbances with respect to age, surgical technique, chemotherapy, and radiotherapy.
By June 2008, 3253 of 3754 eligible women (87%) returned the questionnaire. A total of 1543 patients (47%) reported pain, of whom 201 (13%) had severe pain, 595 (39%) had moderate pain, and 733 (48%) had light pain. Factors associated with chronic pain included young age (18-39 years: OR, 3.62; 95% confidence interval [CI], 2.25-5.82; P < .001) and adjuvant radiotherapy (OR, 1.50; 95% CI, 1.08-2.07; P = .03), but not chemotherapy (OR, 1.01; 95% CI, 0.85-1.21; P = .91). Axillary lymph node dissection (ALND) was associated with increased likelihood of pain (OR, 1.77; 95% CI, 1.43-2.19; P < .001) compared with sentinel lymph node dissection. Risk of sensory disturbances was associated with young age (18-39 years: OR, 5.00; 95% CI, 2.87-8.69; P < .001) and ALND (OR, 4.97; 95% CI, 3.92-6.30; P < .001). Pain complaints from other parts of the body were associated with increased risk of pain in the surgical area (P < .001). A total of 306 patients (20%) with pain had contacted a physician within the prior 3 months for pain complaints in the surgical area.
Two to 3 years after breast cancer treatment, persistent pain and sensory disturbances remain clinically significant problems among Danish women who received surgery in 2005 and 2006.
Previous work has established stargazin and its related family of transmembrane AMPA receptor regulatory proteins (TARPs) as auxiliary subunits of AMPA receptors (AMPARs) that control synaptic strength both by targeting AMPARs to synapses through an intracellular PDZ-binding motif and by modulating their gating through an extracellular domain. However, TARPs gamma-2 and gamma-8 differentially regulate the synaptic targeting of AMPARs, despite having identical PDZ-binding motifs. Here, we investigate the structural elements that contribute to this functional difference between TARP subtypes by using domain transplantation and truncation. We identify a component of synaptic AMPAR trafficking that is independent of the TARP C-terminal PDZ-binding motif, and we establish previously uncharacterized roles for the TARP intracellular N terminus, loop, and C terminus in modulating both the trafficking and gating of synaptic AMPARs.
Migraine is an episodic neurovascular disorder that is clinically divided into two main subtypes that are based on the absence or presence of an aura: migraine without aura (MO) and migraine with aura (MA). Current molecular genetic insight into the pathophysiology of migraine predominantly comes from studies of a rare monogenic subtype of migraine with aura called familial hemiplegic migraine (FHM). Three FHM genes have been identified, which all encode ion transporters, suggesting that disturbances in ion and neurotransmitter balances in the brain are responsible for this migraine type, and possibly the common forms of migraine. Cellular and animal models expressing FHM mutations hint toward neuronal hyperexcitability as the likely underlying disease mechanism. Additional molecular insight into the pathophysiology of migraine may come from other monogenic syndromes (for instance cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, which is caused by NOTCH3 mutations), in which migraine is prominent. Investigating patients with common forms of migraine has had limited successes. Except for 5',10'-methylenetetrahydrolate reductase, an enzyme in folate metabolism, the large majority of reported genetic associations with candidate migraine genes have not been convincingly replicated. Genetic linkage studies using migraine subtypes as an end diagnosis did not yield gene variants thus far. Clinical heterogeneity in migraine diagnosis may have hampered the identification of such variants. Therefore, the recent introduction of more refined methods of phenotyping, such as latent-class analysis and trait component analysis, may be certainly helpful. Combining the new phenotyping methods with genome-wide association studies may be a successful strategy toward identification of migraine susceptibility genes. Likely the identification of reliable biomarkers for migraine diagnosing will make these efforts even more successful.
Gabapentin (Neurontin) and pregabalin (Lyrica) comprise an interesting class of drugs for chronic pain. These drugs differ structurally and mechanistically from other analgesics and also have efficacy in randomized trials for epileptic seizures and anxiety disorders. This paper highlights cellular and molecular mechanisms of these drugs that reduce pain. It is concluded that these drugs are not GABAergic and instead reduce the stimulated release of transmitters by binding at calcium channel alpha2-delta (CaVa2-d) proteins. The CaV nomenclature is useful to avoid confusion with unrelated adrenergic alpha receptors. Recent evidence suggests that CaVa2-d drugs also could reduce activity within certain cellular
signaling pathways.
Poorly controlled cancer pain is a significant public health problem throughout the world. There are many barriers that lead to undertreatment of cancer pain. One important barrier is inadequate measurement and assessment of pain. To address this problem, the Pain Research Group of the WHO Collaborating Centre for Symptom Evaluation in Cancer Care has developed the Brief Pain Inventory (BPI), a pain assessment tool for use with cancer patients. The BPI measures both the intensity of pain (sensory dimension) and interference of pain in the patient's life (reactive dimension). It also queries the patient about pain relief, pain quality, and patient perception of the cause of pain. This paper describes the development of the Brief Pain Inventory and the various applications to which the BPI is suited. The BPI is a powerful tool and, having demonstrated both reliability and validity across cultures and languages, is being adopted in many countries for clinical pain assessment, epidemiological studies, and in studies of the effectiveness of pain treatment.
It is generally acknowledged that humans display highly variable sensitivity to pain, including variable responses to identical injuries or pathologies. The possible contribution of genetic factors has, however, been largely overlooked. An emerging rodent literature documents the importance of genotype in mediating basal nociceptive sensitivity, in establishing a predisposition to neuropathic pain following neural injury, and in determining sensitivity to pharmacological agents and endogenous antinociception. One clear finding from these studies is that the effect of genotype is at least partially specific to the nociceptive assay being considered. In this report we begin to systematically describe and characterize genetic variability of nociception in a mammalian species, Mus musculus. We tested 11 readily-available inbred mouse strains (129/J, A/J, AKR/J, BALB/cJ, C3H/HeJ, C57BL/6J, C58/J, CBA/J, DBA/2J, RIIIS/J and SM/J) using 12 common measures of nociception. These included assays for thermal nociception (hot plate, Hargreaves' test, tail withdrawal), mechanical nociception (von Frey filaments), chemical nociception (abdominal constriction, carrageenan, formalin), and neuropathic pain (autotomy, Chung model peripheral nerve injury). We demonstrate the existence of clear strain differences in each assay, with 1.2 to 54-fold ranges of sensitivity. All nociceptive assays display moderate-to-high heritability (h2 = 0.30-0.76) and mediation by a limited number of apparent genetic loci. Data comparing inbred strains have considerable utility as a tool for understanding the genetics of nociception, and a particular relevance to transgenic studies.
In the study of complex traits, the utility of linkage analysis and single marker association tests can be limited for researchers attempting to elucidate the complex interplay between a gene and environmental covariates. For these purposes, tests of gene-environment interactions are needed. In addition, recent studies have indicated that haplotypes, which are specific combinations of nucleotides on the same chromosome, may be more suitable as the unit of analysis for statistical tests than single genetic markers. The difficulty with this approach is that, in standard laboratory genotyping, haplotypes are often not directly observable. Instead, unphased marker phenotypes are collected. In this article, we present a method for estimating and testing haplotype-environment interactions when linkage phase is potentially ambiguous. The method builds on the work of Schaid et al. [2002] and is applicable to any trait that can be placed in the generalized linear model framework. Simulations were run to illustrate the salient features of the method. In addition, the method was used to test for haplotype-smoking exposure interaction with data from the Childhood Asthma Management Program.
Acute postoperative pain is followed by persistent pain in 10-50% of individuals after common operations, such as groin hernia repair, breast and thoracic surgery, leg amputation, and coronary artery bypass surgery. Since chronic pain can be severe in about 2-10% of these patients, persistent postsurgical pain represents a major, largely unrecognised clinical problem. Iatrogenic neuropathic pain is probably the most important cause of long-term postsurgical pain. Consequently, surgical techniques that avoid nerve damage should be applied whenever possible. Also, the effect of aggressive, early therapy for postoperative pain should be investigated, since the intensity of acute postoperative pain correlates with the risk of developing a persistent pain state. Finally, the role of genetic factors should be studied, since only a proportion of patients with intraoperative nerve damage develop chronic pain. Based on information about the molecular mechanisms that affect changes to the peripheral and central nervous system in neuropathic pain, several opportunities exist for multimodal pharmacological intervention. Here, we outline strategies for identification of patients at risk and for prevention and possible treatment of this important entity of chronic pain.
Considerable evidence has demonstrated that alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor blockade has an antinociceptive effect on inflammatory pain. Stargazin (STG) is the first transmembrane protein known to associate with AMPA receptors and regulate their synaptic targeting. However, it is not known whether STG is involved in inflammatory pain processing by regulating AMPA receptor function. In the present study, we investigated the effect of knockdown of spinal STG on AMPA receptor-mediated pain sensitization after inflammation. Antisense technology was employed to knock down STG expression in the spinal cord. We show that STG was expressed and interacted with AMPA receptor subunit GluR2 in the spinal cord. Intrathecally injected STG antisense oligodeoxyribonucleotide (ODN) specifically decreased STG expression in the lumbar spinal cord and dose dependently inhibited formalin-induced inflammatory pain in the second phase. More important was our finding for the first time that this specific STG antisense ODN diminished AMPA (0.1 mug)-enhanced formalin pain and lost its effect if pretreated with AMPA receptor antagonist CNQX. Our results demonstrate a new role for STG in central sensitization of inflammatory pain by interacting with AMPA receptors in the spinal cord.
Accumulation of AMPA receptors at synapses is a fundamental feature of glutamatergic synaptic transmission. Stargazin, a member of the TARP family, is an AMPAR auxiliary subunit allowing interaction of the receptor with scaffold proteins of the postsynaptic density, such as PSD-95. How PSD-95 and Stargazin regulate AMPAR number in synaptic membranes remains elusive. We show, using single quantum dot and FRAP imaging in live hippocampal neurons, that exchange of AMPAR by lateral diffusion between extrasynaptic and synaptic sites mostly depends on the interaction of Stargazin with PSD-95 and not upon the GluR2 AMPAR subunit C terminus. Disruption of interactions between Stargazin and PSD-95 strongly increases AMPAR surface diffusion, preventing AMPAR accumulation at postsynaptic sites. Furthermore, AMPARs and Stargazin diffuse as complexes in and out synapses. These results propose a model in which the Stargazin-PSD-95 interaction plays a key role to trap and transiently stabilize diffusing AMPARs in the postsynaptic density.
The stargazer (stg) mutant mouse, having mutation in stargazin, the calcium channel gamma2 subunit, exhibited several neurological disorders including spontaneous absence seizure, cerebellar ataxia, and head tossing. To understand the molecular pathogenic mechanism of the absence seizure resulted from the loss of stargazin function, the thalamic proteomes between control mouse and stg mouse were compared. We identified 12 proteins expressed differentially (> 1.6-fold) by fluorescence two-dimensional difference gel electrophoresis and tandem mass spectrometry. Six of them are involved in basic metabolism including energy metabolism, three in stress response, two in axonal growth regulation, and one in the endoplasmic reticulum processing. All except mortalin showed decreased level of expression in stg mouse. Two stress-related proteins, mouse stress induced phosphoprotein 1 and peroxiredoxin 6 exhibited reduced levels of expression in stg mouse, while the level of another stress protein, mortalin was increased. Analysis of oxidative protein carbonylation in thalamic proteome of stg mouse showed higher level of carbonylated proteins in stg mouse than in control mouse. Interestingly, down-regulation of stress protein mouse stress induced phosphoprotein 1, metabolic enzyme isovaleryl-CoA dehydrogenase, and the two in neuronal axon growth, collapsin response mediator protein 2 and fascin homolog 1 coincides with the results of our previous study on gamma-butyrolactone-induced transient absence seizure. Our results suggest that the pathogenesis mechanism underlying absence seizure may involve the molecular events contributed by these proteins.
Presynaptic ionotropic receptors and control of transmitter release
- Engelman
Pain assessment: global use of the Brief Pain Inventory
- Cleeland