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OBJECTIVE: Thoracic surgery is associated with one of the highest rates of chronic postsurgical pain (CPSP) among all surgical subtypes. Chronic postsurgical pain carries significant medical, psychological, and economic consequences, and further interventions are needed to prevent its development. This study aimed to determine the prevalence, characteristics, and risk factors associated with CPSP after thoracic surgery. DESIGN: A prospective cohort study. SETTING: Single-center tertiary care hospital. PARTICIPANTS: This study included 285 adult patients who underwent thoracic surgery at Toronto General Hospital in Toronto, Canada, between 2012 and 2020. MEASUREMENTS AND MAIN RESULTS: Demographic, psychological, and clinical data were collected perioperatively, and follow-up evaluations were administered at 3, 6, and 12 months after surgery to assess CPSP. Chronic postsurgical pain was reported in 32.4%, 25.4%, and 18.2% of patients at 3, 6, and 12 months postoperatively, respectively. Average CPSP pain intensity was rated to be 3.37 (SD 1.82) at 3 months. Features of neuropathic pain were present in 48.7% of patients with CPSP at 3 months and 71% at 1 year. Multivariate logistic regression models indicated that independent predictors for CPSP at 3 months were scores on the Hospital Anxiety and Depression Scale (adjusted odds ratio [aOR] of 1.07, 95% CI of 1.02 to 1.14, p = 0.012) and acute postoperative pain (aOR of 2.75, 95% CI of 1.19 to 6.36, p = 0.018). INTERVENTIONS: None. CONCLUSIONS: Approximately 1 in 3 patients will continue to have pain at 3 months after surgery, with a large proportion reporting neuropathic features. Risk factors for pain at 3 months may include preoperative anxiety and depression and acute postoperative pain.
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Dolor Crónico , Dolor Postoperatorio , Procedimientos Quirúrgicos Torácicos , Humanos , Masculino , Femenino , Estudios Prospectivos , Dolor Postoperatorio/epidemiología , Dolor Postoperatorio/psicología , Dolor Postoperatorio/etiología , Dolor Postoperatorio/diagnóstico , Factores de Riesgo , Dolor Crónico/epidemiología , Dolor Crónico/etiología , Dolor Crónico/psicología , Persona de Mediana Edad , Prevalencia , Procedimientos Quirúrgicos Torácicos/efectos adversos , Anciano , Estudios de Cohortes , Adulto , Estudios de SeguimientoRESUMEN
BACKGROUND AND METHODS: Pregabalin alleviates stimulus-evoked neuropathic pain (NeuP) in some pain patients and rodents in models of painful neuropathies. But it is not known if pregabalin can also alleviate spontaneous NeuP. Sciatic and saphenous neurectomy in rats elicits spontaneous self-mutilation of the denervated hindpaw, a behavior that models spontaneous NeuP. We tested if pregabalin (20 or 30 mg/kg/day; twice daily, per os) for 7 days before denervation, or 42 days thereafter, can suppress this behavior. RESULTS: Compared with the vehicle, pregabalin administered in both treatment regimens markedly and significantly delayed autotomy onset and suppressed its levels for weeks after treatment cessation. CONCLUSIONS: At doses known to effectively suppress stimulus-evoked pain in rats, pregabalin can prevent development of spontaneous NeuP and suppress it postoperatively.
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Analgésicos/administración & dosificación , Analgésicos/uso terapéutico , Neuralgia/tratamiento farmacológico , Neuralgia/prevención & control , Pregabalina/administración & dosificación , Pregabalina/uso terapéutico , Administración Oral , Animales , Conducta Animal/efectos de los fármacos , Masculino , Ratas Sprague-Dawley , Nervio Ciático/lesionesRESUMEN
PURPOSE: Most patients who undergo surgery or experience a traumatic injury suffer from acute pain that subsides once tissues heal. Nevertheless, the pain remains in 15-30% of patients, sometimes for life, and this chronic post-surgical pain (CPSP) can result in suffering, depression, anxiety, sleep disturbance, physical incapacitation, and an economic burden. The incorporation of genetic knowledge is expected to lead to the development of more effective means to prevent and manage CPSP using tools of personalized pain medicine. The purpose of this review article is to provide an update on the current state of CPSP genetics and its future potential. PRINCIPLE FINDINGS: The large variability in CPSP amongst patients undergoing similar surgery suggests that individual factors are significant contributors to CPSP, raising the possibility that CPSP is influenced by genetic determinants. Heritability estimates suggest that about half of the variance in CPSP levels is attributable to genetic variation. These estimates suggest that identifying the genetic underpinnings of CPSP may lead to significant improvements in treatment. Analyzing patients' DNA sequences, blood and salivary pain biomarkers, as well as their analgesic responses to medications will facilitate developing insights into CPSP pathophysiology and inform predictive algorithms to determine a patient's likelihood of developing CPSP even prior to surgery. These algorithms could facilitate effective treatment regimens that will protect against the transition to chronicity in traumatically injured patients or those scheduled for surgery and lead to better therapy for patients who have already developed CPSP. CONCLUSIONS: Pharmacogenomic technologies and strategies provide an opportunity to expand our knowledge in CPSP treatment that may manifest in a personalized approach to diagnosis, prevention, and therapy. Capitalizing on this genomic knowledge will necessitate the analysis of many tens of thousands of study patients. This will require an international coordinated effort to which anesthesiologists and surgeons can contribute substantially.
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Manejo del Dolor/métodos , Dolor Postoperatorio/tratamiento farmacológico , Dolor Postoperatorio/genética , Dolor Crónico/tratamiento farmacológico , Dolor Crónico/genética , Humanos , Factores de RiesgoRESUMEN
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.
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Canales de Calcio/genética , Neuralgia/genética , Animales , Canales de Calcio/metabolismo , Estudios de Cohortes , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Ratones , Ratones Endogámicos , Fenotipo , Polimorfismo Genético , Sitios de Carácter Cuantitativo , Nervios Espinales/lesionesRESUMEN
ABSTRACT: Chronic postsurgical pain (CPSP) and disability after cardiothoracic surgery are highly prevalent and difficult to treat. Researchers have explored a variety of presurgical risk factors for CPSP and disability after cardiothoracic surgery, including one study that examined distress from bodily sensations. The current prospective, longitudinal study sought to extend previous research by investigating presurgical distress about bodily sensations as a risk factor for CPSP and disability after cardiothoracic surgery while controlling for several other potential psychosocial predictors. Participants included 543 adults undergoing nonemergency cardiac or thoracic surgery who were followed over 6 months postsurgically. Before surgery, participants completed demographic, clinical, and psychological questionnaires. Six months after surgery, participants reported the intensity of CPSP on a 0 to 10 numeric rating scale and pain disability, measured by the Pain Disability Index. Multinomial logistic regression analyses were conducted to evaluate the degree to which presurgical measures predicted pain outcomes 6 months after surgery. The results showed that CPSP intensity was significantly predicted by age and presurgical scores on the Symptom Checklist-90-Revised Somatization subscale (Nagelkerke R2 = 0.27, P < 0.001), whereas chronic pain disability was only predicted by presurgical Symptom Checklist-90-Revised Somatization scores (Nagelkerke R2 = 0.29, P < 0.001). These findings demonstrate that presurgical distress over bodily sensations predicts greater chronic pain intensity and disability 6 months after cardiothoracic surgery and suggest that presurgical treatment to diminish such distress may prevent or minimize CPSP intensity and disability.
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Dolor Crónico , Dolor Postoperatorio , Adulto , Dolor Crónico/etiología , Humanos , Estudios Longitudinales , Dimensión del Dolor , Dolor Postoperatorio/etiología , SensaciónRESUMEN
Not all patients with nerve injury develop neuropathic pain. The extent of nerve damage and age at the time of injury are two of the few risk factors identified to date. In addition, preclinical studies show that neuropathic pain variance is heritable. To define such factors further, we performed a large-scale gene profiling experiment which plotted global expression changes in the rat dorsal root ganglion in three peripheral neuropathic pain models. This resulted in the discovery that the potassium channel alpha subunit KCNS1, involved in neuronal excitability, is constitutively expressed in sensory neurons and markedly downregulated following nerve injury. KCNS1 was then characterized by an unbiased network analysis as a putative pain gene, a result confirmed by single nucleotide polymorphism association studies in humans. A common amino acid changing allele, the 'valine risk allele', was significantly associated with higher pain scores in five of six independent patient cohorts assayed (total of 1359 subjects). Risk allele prevalence is high, with 18-22% of the population homozygous, and an additional 50% heterozygous. At lower levels of nerve damage (lumbar back pain with disc herniation) association with greater pain outcome in homozygote patients is P = 0.003, increasing to P = 0.0001 for higher levels of nerve injury (limb amputation). The combined P-value for pain association in all six cohorts tested is 1.14 E-08. The risk profile of this marker is additive: two copies confer the most, one intermediate and none the least risk. Relative degrees of enhanced risk vary between cohorts, but for patients with lumbar back pain, they range between 2- and 3-fold. Although work still remains to define the potential role of this protein in the pathogenic process, here we present the KCNS1 allele rs734784 as one of the first prognostic indicators of chronic pain risk. Screening for this allele could help define those individuals prone to a transition to persistent pain, and thus requiring therapeutic strategies or lifestyle changes that minimize nerve injury.
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Canal de Potasio Kv.1.1/genética , Dolor/genética , Polimorfismo Genético/genética , Valina/genética , Animales , Enfermedad Crónica , Estudios de Cohortes , Comprensión , Biología Computacional/métodos , Comparación Transcultural , Modelos Animales de Enfermedad , Femenino , Ganglios Espinales/metabolismo , Ganglios Espinales/patología , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Desequilibrio de Ligamiento , Masculino , Proteínas de Neurofilamentos , Neuropéptidos/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Dolor/etiología , RatasRESUMEN
The classic definition of preemptive analgesia requires 2 groups of patients to receive identical treatment before or after incision or surgery. The only difference between the 2 groups is the timing of administration of the drug relative to incision. The constraint to include a postincision or postsurgical treatment group is methodologically appealing, because in the presence of a positive result, it provides a window of time within which the observed effect occurred, and thus points to possible mechanisms underlying the effect: the classic view assumes that the intraoperative nociceptive barrage contributes to a greater extent to postoperative pain than does the postoperative nociceptive barrage. However, this view is too restrictive and narrow, in part because we know that sensitization is induced by factors other than the peripheral nociceptive barrage associated with incision and subsequent noxious intraoperative events. A broader approach to the prevention of postoperative pain has evolved that aims to minimize the deleterious immediate and long-term effects of noxious perioperative afferent input. The focus of preventive analgesia is not on the relative timing of analgesic or anesthetic interventions, but on attenuating the impact of the peripheral nociceptive barrage associated with noxious preoperative, intraoperative, and/or postoperative stimuli. These stimuli induce peripheral and central sensitization, which increase postoperative pain intensity and analgesic requirements. Preventing sensitization will reduce pain and analgesic requirements. Preventive analgesia is demonstrated when postoperative pain and/or analgesic use are reduced beyond the duration of action of the target drug, which we have defined as 5.5 half-lives of the target drug. This requirement ensures that the observed effects are not direct analgesic effects. In this article, we briefly review the history of preemptive analgesia and relate it to the broader concept of preventive analgesia. We highlight clinical trial designs and examples from the literature that distinguish preventive analgesia from preemptive analgesia and conclude with suggestions for future research.
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Analgesia , Dolor Postoperatorio/prevención & control , Enfermedad Aguda , Analgésicos/farmacocinética , Analgésicos/uso terapéutico , Enfermedad Crónica , Historia del Siglo XX , Humanos , Dolor Postoperatorio/epidemiología , Dolor Postoperatorio/historia , Factores de RiesgoRESUMEN
PURPOSE: Individuals with Sensory Modulation Disorder (SMD) are characterized by an inability to normally grade the degree, intensity and nature of their responses to sensory input and are limited in their ability to fully participate in daily life activities, and attain optimal quality of life. Most existing diagnostic tools are intended for paediatric populations. A questionnaire that assesses the intensity of the affective-emotive responsiveness of adults to stimuli in all sensory modalities and the frequency of such responses for diagnosing adults with disorders in sensory modulation is necessary. This article describes the development and assessment of the psychometric properties of a novel instrument, the Sensory Responsiveness Questionnaire (SRQ), for this purpose (see Appendix). METHOD: The SRQ evolved through three developmental phases (Pilot, Version-I, and the most recent Version-II). Each phase comprised several studies conducted to further refine the instrument and to examine its psychometric properties with adults with Sensory Modulation Disorder versus SMD-free individuals (n=39 for the pilot version, n=399 for Version-I, and n=48 for Version-II). RESULTS: The scales of Version-II indicated high test-retest reliability, moderate criterion validity and strong significant construct validity. CONCLUSION: There is strong indication that the SRQ can be used to diagnose adults with SMD.
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Trastornos de la Sensación/diagnóstico , Encuestas y Cuestionarios , Actividades Cotidianas , Adulto , Análisis de Varianza , Femenino , Humanos , Masculino , Persona de Mediana Edad , Psicometría , Calidad de Vida , Reproducibilidad de los Resultados , Trastornos de la Sensación/psicologíaRESUMEN
Phantom limb (PLP) as well as residual limb pain (RLP) are still a very significant problem after amputation and their causes are only partially known. Here we tested whether the predisposition for the frequency, duration and intensity of PLP and RLP is shared with other prior chronic pains and/or the presence of postamputation subacute pain. A week preoperatively we collected data using validated questionnaires, a pain diary and interviews on past chronic pain conditions, acute pain, depression, anxiety, pain interference, life control, social support and affective distress and pain ratings one day before the amputation in 52 patients scheduled for limb amputation. In the week postamputation and again three and 12 months thereafter, we collected data on postoperative wound pain, PLP, RLP and non-painful phantom sensation (PLS). Phantom and residual limb pain indices were calculated per patient, integrating the intensity, frequency and duration of past chronic pain, PLP, RLP and PLS into a single value to index the overall burden of pain. We report that acute and chronic pain long before but not on the day before the amputation and subacute pain postamputation significantly predicted up to half of the variance in the incidence and severity of PLP, RLP and PLS 12 months postamputation. Moreover, the severity of these painful sensations at 12 months postamputation was partially predicted by preamputation scores of depression and anxiety. These findings corroborate the hypothesis that chronic pain and non-painful sensations following limb amputation are strongly related to longstanding preoperative chronic pain and to subacute postoperative pain as well as to psychological factors before the amputation that may be inherited and/or acquired (learning- and memory-related). Furthermore, we also confirm that subacute pain postamputation comprises an additional risk factor for long-term painful sensations postamputation. Our results suggest that timely interventions might prevent the development of chronic pain.
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Miembro Fantasma/fisiopatología , Enfermedad Aguda , Anciano , Analgésicos/uso terapéutico , Enfermedad Crónica , Femenino , Humanos , Masculino , Persona de Mediana Edad , Manejo del Dolor , Dimensión del Dolor , Miembro Fantasma/tratamiento farmacológico , Miembro Fantasma/psicología , Periodo Posoperatorio , Periodo PreoperatorioRESUMEN
Background: Despite the same surgical approach, up to 40% of patients develop chronic postsurgical pain (CPSP) following cardiac surgery, whereas the rest are chronic pain free. This variability suggests that CPSP is controlled partially through genetics, but the genes for CPSP are largely unknown. Aims: The aim of this study was to identify potential CPSP phenotypes by comparing patients who developed CPSP following cardiac surgery vs. those who did not. Methods: A research ethics board-approved, cross-sectional study of post-cardiac surgery pain was conducted at Toronto General Hospital from 2011 to 2015. Patients were recruited to complete a short survey of chronic pain scores and the Short-Form McGill Pain Questionnaire-2. A subset of patients completed a longer survey of eight validated pain phenotyping questionnaires and/or four psychophysical assessments. All surveys and psychophysical testing were conducted after surgery. Patients were stratified by presence of chronic pain and groups were compared using descriptive statistics. Results: Six hundred forty-three patients completed the short form survey. The mean postsurgery assessment time was 41.5 (SD = ±25.1) months. Over a quarter (27.8%) reported CPSP at the chest as a consequence of their surgery. Of patients reporting CPSP, 46.6% reported mild pain (0-3), 35.8% reported moderate pain (4-7), and 17.6% reported severe pain (7-10) in accordance with the numerical rating scale. Patients with moderate and/or severe CPSP were younger, had a greater body mass index, and had higher anxiety sensitivity, pain catastrophizing, and somatization scores. Conclusions: Chronic pain levels after cardiac surgery are associated with anxiety, catastrophizing, and sensory abnormalities in body parts outside the field innervated by injured nerves, indicating the presence of widespread central sensitization to incoming sensory inputs from intact nerves.
Contexte: Malgré qu'ils aient été soumis à la même approche chirurgicale, jusqu'à 40 % des patients souffrent de douleur chronique postopératoire après une chirurgie cardiaque, tandis que le reste des patients n'en souffrent pas. Cette variabilité porte à croire que la douleur chronique postopératoire est en partie maitrisée génétiquement, mais les gènes en cause dans la douleur chronique postopératoire sont très peu connus.But: Identifier les phénotypes de douleur chronique postopératoire possibles en comparant des patients souffrant de douleur chronique postopératoire à des patients n'en souffrant pas après une chirurgie cardiaque.Méthodes: Une étude transversale de la douleur après une chirurgie cardiaque approuvée par la commission d'éthique de la recherche a été menée à l'Hôpital général de Toronto de 2011 à 2015. Les patients ont été recrutés pour répondre à un court questionnaire portant sur les scores de douleur chronique et à une version abrégée du McGill Pain Questionnaire-2. Un sous-ensemble de patients a répondu à une enquête plus longue comprenant huit questionnaires validés portant sur le phénotypage de la douleur et/ou sur quatre mesures psychophysiques. Tous les questionnaires et les tests psychophysiques ont été menés après la chirurgie. Les patients ont été stratrifiés en fonction de la présence de douleur chronique et les groupes ont été comparés à l'aide de statistiques descriptives.Résultats: 634 patients ont répondu à la version courte de l'enquête. Le temps moyen de l'évaluation post-chirurgie était de 41,4 mois (écart-type ± 25,1). Plus d'un quart (27,8%) des participants ont rapporté de la douleur chronique postopératoire au thorax en tant que conséquence de la chirurgie. Parmi les patients rapportant de la douleur chronique post-opératoire, 46,6 % ont rapporée une douleur faible (0-3), 35,8 % ont rapporté de la douleur modérée (4-7) et 17,6 % ont rapporté de la douleur sévère (7-10), selon l'échelle d'évaluation numérique. Les patients souffrant de douleur chronique postopératoire de modérée à sévère étaient plus jeunes, avaient un indice de masse corporelle plus élevé et obtenaient des scores plus élevés en ce qui concerne la sensibilité à l'anxiété, la catastrophisation de la douleur et la somatisation.Conclusion: Les niveaux de douleur chronique après une chirurgie cardiaque sont associés à l'anxiété, à la catastrophisation et à des anomalies sensorielles dans des parties du corps à l'extérieur de la zone innervée par les nerfs par les nerfs endommagés, ce qui indique la présence d'une sensibilisation centrale généralisée aux signaux sensoriels provenant des nerfs intacts.
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We reported previously that C-fibers innervating rat skin can be excited by short trains of electrical shocks ('tetanus') applied to neighboring nerves. Since these nerves were disconnected from the CNS, the cross-talk is located peripherally. Here we tested if low-threshold mechanoceptive (LTM) C-fibers can be excited by this cross-talk and if this process is mediated by substance P (SP) via neurokinin-1 (NK-1) receptors. In urethane anesthetized rats we found that 80% (56/71) of LTM C-fibers, recorded in the lateral cutaneous branch of the dorsal ramus (CBDR) of T10 spinal nerve, were excited by a 10s, 20 Hz tetanus of the T9 CBDR. Compared to the spontaneous pre-tetanic firing frequency of 1.62+/-0.40 impulses/30s, the frequency significantly increased to 3.74+/-0.99, 3.17+/-0.69 and 2.92+/-0.63 impulses/30s, at 30, 60 and 90 s after the tetanus, respectively, and declined to the baseline frequency thereafter. When injected into their receptive fields, SP mimicked the tetanically induced increase of firing rate, whereas the NK-1 receptor antagonist WIN 51708 blocked the excitation in most fibers. The excitation was significantly diminished in adult rats that were neonatally treated with capsaicin, a treatment that destroys most SP-expressing afferent fibers. Thus, we conclude that peptidergic primary afferents are functionally linked with adjacent LTM C-fibers in a non-synaptic, paracrine-like signaling pathway via SP and NK-1 receptors, and perhaps also other agents as well. We propose that this cross-talk has evolved as a mechanism regulating the mechanoceptive characteristics of LTM C-fibers, presumably contributing to pain sensation elicited by tactile stimuli ('allodynia').
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Mecanorreceptores/fisiología , Fibras Nerviosas Amielínicas/fisiología , Receptores de Neuroquinina-1/fisiología , Piel/inervación , Sustancia P/farmacología , Potenciales de Acción/efectos de los fármacos , Potenciales de Acción/efectos de la radiación , Androstanos/farmacología , Animales , Bencimidazoles/farmacología , Capsaicina/farmacología , Relación Dosis-Respuesta en la Radiación , Estimulación Eléctrica/métodos , Masculino , Fibras Nerviosas Amielínicas/efectos de los fármacos , Fibras Nerviosas Amielínicas/efectos de la radiación , Antagonistas del Receptor de Neuroquinina-1 , Neuronas Aferentes , Ratas , Ratas Sprague-Dawley , Umbral Sensorial/efectos de los fármacos , Umbral Sensorial/fisiología , Umbral Sensorial/efectos de la radiación , Factores de TiempoRESUMEN
Tooth loss is associated with altered sensory, motor, cognitive and emotional functions. These changes vary highly in the population and are accompanied by structural and functional changes in brain regions mediating these functions. It is unclear to what extent this variability in behavior and function is caused by genetic and/or environmental determinants and which brain regions undergo structural plasticity that mediates these changes. Thus, the overall goal of our research program is to identify genetic variants that control structural and functional plasticity following tooth loss. As a step toward this goal, here our aim was to determine whether structural magnetic resonance imaging (sMRI) is sensitive to detect quantifiable volumetric differences in the brains of mice of different genetic background receiving tooth extraction or sham operation. We used 67 adult female mice of 7 strains, comprising the A/J (A) and C57BL/6J (B) strains and a randomly selected sample of 5 of the 23 AXB-BXA strains (AXB1, AXB4, AXB24, BXA14, BXA24) that were produced from the A and B parental mice by recombinations and inbreeding. This panel of 25 inbred strains of genetically diverse inbred strains of mice is used for mapping chromosomal intervals throughout the genome that harbor candidate genes controlling the phenotypic variance of any trait under study. Under general anesthesia, 39 mice received extraction of 3 right maxillary molar teeth and 28 mice received sham operation. On post-extraction day 21, post-mortem whole-brain high-resolution sMRI was used to quantify the volume of 160 brain regions. Compared to sham operation, tooth extraction was associated with a significantly reduced regional and voxel-wise volumes of cortical brain regions involved in processing somatosensory, motor, cognitive and emotional functions, and increased volumes in subcortical sensorimotor and temporal limbic forebrain regions including the amygdala. Additionally, comparison of the 10 BXA14 and 21 BXA24 mice revealed significant volumetric differences between the two strains in several brain regions. These findings highlight the utility of high-resolution sMRI for studying tooth loss-induced structural brain plasticity in mice, and provide a foundation for further phenotyping structural brain changes following tooth loss in the full AXB-BXA panel to facilitate mapping genes that control brain plasticity following orofacial injury.
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Neutrophil recruitment (NR) to sites of sterile inflammation plays a key role in tissue damage and healing potential of lesions characteristic to non-infectious inflammatory diseases. Previous studies suggested significant genetic control of neutrophil survival, function, and migration in inflammatory responses to endogenous and exogenous stimuli. We have mapped the murine genome for quantitative trait loci (QTLs) harbouring genetic determinants that regulate NR in SI using a murine model of chemically-induced peritonitis. NR was quantified in 16 AXB-BXA recombinant inbred strains and their progenitors, A/J (A) and C57BL/6J (B). A continuous distribution of NR was found among the strains, with parent B showing higher NR and parent A showing lower NR (3.0-fold difference, p=0.05). Within the progeny strains, a 5.5-fold difference in NR was observed between the lowest, BXA1, and the highest responders AXB19 (p<0.001). This data was analyzed using GeneNetwork, which linked NR to one significant QTL on chromosome 12 (Peritoneal Neutrophil Recruitment 1, PNR1) and two suggestive QTLs (PNR2, PNR3) on chromosomes 12 and 16 respectively. Sixty-four candidate genes within PNR1 were cross-referenced with currently published data, mRNA expression from two NR microarrays, and single nucleotide polymorphism analysis. The present study brings new light into the genetics of NR in response to cell injury and highlights potential candidate genes Hif1α, Fntb, and Prkch and their products for further studies on neutrophil infiltration and inflammation resolution in sterile inflammation.
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Inflamación/genética , Infiltración Neutrófila/genética , Sitios de Carácter Cuantitativo , Animales , Mapeo Cromosómico , Análisis por Conglomerados , Modelos Animales de Enfermedad , Epistasis Genética , Genotipo , Inflamación/patología , Masculino , Ratones , Ratones Endogámicos , Peritonitis/genética , Peritonitis/patología , Polimorfismo de Nucleótido SimpleRESUMEN
BACKGROUND: Total knee arthroplasty (TKA) is a common and costly surgical procedure. Despite high success rates, many TKA patients develop chronic pain in the months and years following surgery, constituting a public health burden. Pain catastrophizing is a construct that reflects anxious preoccupation with pain, inability to inhibit pain-related fears, amplification of the significance of pain vis-à-vis health implications, and a sense of helplessness regarding pain. Recent research suggests that it may be an important risk factor for untoward TKA outcomes. To clarify this impact, we systematically reviewed the literature to date on pain catastrophizing as a prospective predictor of chronic pain following TKA. METHODS: We searched MEDLINE, EMBASE, and PsycINFO databases to identify articles related to pain catastrophizing, TKA, risk models, and chronic pain. We reviewed titles and abstracts to identify original research articles that met our specified inclusion criteria. Included articles were then rated for methodological quality. including methodological quality. Due to heterogeneity in follow-up, analyses, and outcomes reported across studies, a quantitative meta-analysis could not be performed. RESULTS: We identified six prospective longitudinal studies with small-to-mid-sized samples that met the inclusion criteria. Despite considerable variability in reported pain outcomes, pain catastrophizing was identified as a significant predictor of chronic pain persisting ≥3 months following TKA in five of the studies assessed. Limitations of studies included lack of large-scale data, absence of standardized pain measurements, inadequate multivariate adjustment, such as failure to control for analgesic use and other relevant covariates, and failure to report non-significant parameter estimates. CONCLUSION: This study provides moderate-level evidence for pain catastrophizing as an independent predictor of chronic pain post-TKA. Directions for future research include larger, well-controlled studies with standard pain outcomes, identification of clinically-relevant catastrophizing cut-offs that predict pain outcomes, investigation of other psychosocial risk factors, and assessment of interventions aimed to reduce pain catastrophizing on chronic pain outcomes following TKA surgery.
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UNLABELLED: Most, but not all, limb amputees develop phantom limb pain (PLP) or residual limb pain (RLP), and large interindividual differences in pain intensity and course are apparent. The present cross-sectional study of 122 double amputees investigated the possible role of genetic factors in PLP and RLP, assuming that strong individual predisposition results in high intraindividual concordance in pain phenotype. Intraindividual concordance was observed in 116 (95%) patients for development of PLP and in 110 patients (90%) for development of RLP. For both pain types, high intraindividual concordance was also observed for remission and current intensity. Moderate association for lifetime history and current intensity of PLP and RLP was observed both within and between limbs. The high intraindividual concordance in pain phenotypes suggests strong individual predisposition for PLP and RLP development. However, the finding of only moderate association between PLP and RLP suggests that susceptibility to these pain phenomena involves distinct, as well as common, risk factors. Genome-wide studies in large samples of single amputees may facilitate the dissection of these phenotypes and their underlying mechanisms. PERSPECTIVE: The observation of high intraindividual concordance for PLP and RLP in 122 double amputees suggests that individual factors contribute to post-amputation pain. The relatively low intraindividual association between PLP and RLP suggests that these factors are at least partially specific for each pain type.
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Amputación Quirúrgica/efectos adversos , Amputados , Predisposición Genética a la Enfermedad , Miembro Fantasma/genética , Adulto , Anciano , Anciano de 80 o más Años , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neuralgia/genética , Dimensión del Dolor , Miembro Fantasma/fisiopatología , Fenotipo , Factores de Riesgo , Encuestas y Cuestionarios , Adulto JovenRESUMEN
For genetic research to contribute more fully to furthering our knowledge of neuropathic pain, we require an agreed, valid, and feasible approach to phenotyping, to allow collaboration and replication in samples of sufficient size. Results from genetic studies on neuropathic pain have been inconsistent and have met with replication difficulties, in part because of differences in phenotypes used for case ascertainment. Because there is no consensus on the nature of these phenotypes, nor on the methods of collecting them, this study aimed to provide guidelines on collecting and reporting phenotypes in cases and controls for genetic studies. Consensus was achieved through a staged approach: (1) systematic literature review to identify all neuropathic pain phenotypes used in previous genetic studies; (2) Delphi survey to identify the most useful neuropathic pain phenotypes and their validity and feasibility; and (3) meeting of experts to reach consensus on the optimal phenotype(s) to be collected from patients with neuropathic pain for genetic studies. A basic "entry level" set of phenotypes was identified for any genetic study of neuropathic pain. This set identifies cases of "possible" neuropathic pain, and controls, and includes: (1) a validated symptom-based questionnaire to determine whether any pain is likely to be neuropathic; (2) body chart or checklist to identify whether the area of pain distribution is neuroanatomically logical; and (3) details of pain history (intensity, duration, any formal diagnosis). This NeuroPPIC "entry level" set of phenotypes can be expanded by more extensive and specific measures, as determined by scientific requirements and resource availability.
Asunto(s)
Consenso , Técnica Delphi , Testimonio de Experto/normas , Cooperación Internacional , Neuralgia , Bases de Datos Bibliográficas/estadística & datos numéricos , Testimonio de Experto/métodos , Humanos , Neuralgia/diagnóstico , Neuralgia/genética , Neuralgia/fisiopatología , Dimensión del Dolor , FenotipoRESUMEN
In a previous report we presented a novel behavioral model of neuropathic pain disorders, produced in rat by a unilateral ligation of about half of the sciatic nerve. The model is characterized by rapid onset of behaviors suggesting spontaneous pain and disordered responses to non-noxious and noxious stimuli. These include reduced withdrawal thresholds to repetitive touch in the partially deafferented skin ('touched-evoked hyperesthesia'), touch-evoked allodynia, reduced withdrawal thresholds to noxious thermal stimuli and exaggerated responses to noxious heat and mechanical stimuli ('thermal hyperalgesia'). Some of these disorders are seen at mirror image sites on the hind limb opposite the lesion. These disorder start within hours after partial nerve injury, last many months and are very similar to causalgia in humans following partial nerve injury. Since sympathetic efferent activity is known to aggravate causalgia in humans and sympathectomy is known to relieve it, we studied the effect of changing sympathetic outflow in the rat model. Reversible sympathectomy was carried out using guanethidine injected intraperitoneally in 3 experiments, each at a different time in relation to the partial nerve injury. We found that: (1) sympathectomy performed several months postoperatively alleviated the sensory disorders bilaterally; (2) sympathectomy prior to nerve injury partially prevented the appearance of thermal hyperalgesia but did not affect hyperesthesia to repetitive touch; and (3) sympathectomy at the time of nerve injury aggravated the sensory disorders during the first few days. As maintenance and production of the sensory disorders in this animal model depended on sympathetic nervous outflow, we conclude that the rats were suffering from a syndrome analogous to sympathetically maintained causalgia in man.
Asunto(s)
Causalgia/fisiopatología , Nervio Ciático/lesiones , Simpatectomía , Animales , Conducta Animal/fisiología , Causalgia/etiología , Calor , Masculino , Ratas , Nervio Ciático/cirugía , Umbral Sensorial/fisiología , TactoRESUMEN
Partial nerve injury is the main cause of causalgiform pain disorders in humans. We present here a novel animal model of this condition. In rats we unilaterally ligated about half of the sciatic nerve high in the thigh. Within a few hours after the operation, and for several months thereafter, the rats developed guarding behavior of the ipsilateral hind paw and licked it often, suggesting the possibility of spontaneous pain. The plantar surface of the foot was evenly hyperesthetic to non-noxious and noxious stimuli. None of the rats autotomized. There was a sharp decrease in the withdrawal thresholds bilaterally in response to repetitive Von Frey hair stimulation at the plantar side. After a series of such stimuli in the operated side, light touch elicited aversive responses, suggesting allodynia to touch. The withdrawal thresholds to CO2 laser heat pulses were markedly lowered bilaterally. Suprathreshold noxious heat pulses elicited exaggerated responses unilaterally, suggesting thermal hyperalgesia. Pin-prick evoked such exaggerated responses bilaterally (mechanical hyperalgesia). In a companion report, we show that these abnormalities critically depend on the sympathetic outflow. Based on the immediate onset and long-lasting perpetuation of similar symptoms, such as touch-evoked allodynia and hyperalgesia, and the resemblance of the contralateral phenomena to 'mirror image' pains in some humans with causalgia, we suggest that this preparation may serve as a model for syndromes of the causalgiform variety that are triggered by partial nerve injury and maintained by sympathetic activity.
Asunto(s)
Conducta Animal , Causalgia/fisiopatología , Nervio Ciático/lesiones , Animales , Causalgia/etiología , Modelos Animales de Enfermedad , Traumatismos de los Pies , Marcha , Miembro Posterior , Humanos , Masculino , Postura , Ratas , Nervio Ciático/cirugía , TactoRESUMEN
When a peripheral nerve is severed, damaged sensory fibers emit a barrage of impulses that lasts for many seconds, or even several minutes ('injury discharge'). We have shown in rats that local anesthetic blockade of this discharge suppresses autotomy (a behavioral model of neuropathic pain). Correspondingly, mimicking prolonged injury discharge with electrical stimulation, especially of C-fibers, increased autotomy. These data support the hypothesis that injury discharge plays a role in the triggering of neuropathic pain. The mechanism of triggering autotomy was investigated using intrathecal injection of agents affecting glutamatergic transmission. A single intrathecal injection at the lumbar enlargement of the NMDA receptor blockers MK-801 and 5-APV, just prior to neurectomy, significantly suppressed autotomy. Blocking glycinergic inhibition just prior to neurectomy with a single strychnine injection strikingly enhanced autotomy. Strychnine enhancement of autotomy was prevented by prior injection of MK-801 or 5-APV. These results suggest that the expression of autotomy in rats, and by inference neuropathic pain in humans, is affected by injury discharge, possibly mediated by long-lasting, NMDA receptor-related, spinal disinhibition.
Asunto(s)
Conducta Animal/efectos de los fármacos , Dolor/psicología , Traumatismos de los Nervios Periféricos , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Médula Espinal/fisiología , 2-Amino-5-fosfonovalerato/farmacología , Animales , Conducta Animal/fisiología , Maleato de Dizocilpina/farmacología , Estimulación Eléctrica , Glutamatos/fisiología , Ácido Glutámico , Glicina/fisiología , Inyecciones Espinales , Masculino , Dolor/tratamiento farmacológico , Ratas , Estricnina/administración & dosificación , Estricnina/farmacologíaRESUMEN
When sensory fibers are damaged, a discharge of impulses is emitted, which can last up to a few minutes. In the present study, we examined whether this injury discharge plays a role in triggering 'autotomy'--a behavior involving self-injury in animals that is induced by total denervation of a hind paw. Sensory input from the sciatic and saphenous neuroma is thought to elicit chronic pain sensations which cause the rat to injure the hind paw. In the present experiments: (1) injury discharge was prevented by using a local anesthetic block and (2) injury discharge was artificially prolonged by delivering 150 electrical pulses to the nerve just prior to transection, at a strength sufficient to drive A- and C-fibers. In one group of animals, the nerve was stimulated at 0.5 Hz at which frequency a synchronous, repetitive activity in C-fibers augments the response of some nociceptive dorsal horn neurons by temporal summation ('wind-up'). In 2 other groups, the sciatic nerve was stimulated at 0.1 Hz and 10 Hz. The results show that blocking injury discharge significantly delayed the average time of onset of autotomy and suppressed it in magnitude compared to control rats. In contrast, electrical stimulation, especially at the 'wind-up' frequency, significantly shortened the onset of autotomy and enhanced its severity. Thus, in spite of its short duration, injury discharge affects the subsequent development of neuropathic pain related behavior.