Pain Study in X-Linked Adrenoleukodystrophy in Males and Females.

INTRODUCTION: X-linked adrenoleukodystrophy (ALD) is a metabolic disorder in which very long chain fatty acids (VLCFAs) are accumulated in the nervous system and adrenal cortex, impairing their functions. Three main variants are described in males: adrenomyeloneuropathy (AMN), a cerebral form (cALD or cAMN) and Addison's disease only (AD), while for females no classification is used. To evaluate pain and the functional state of afferent fibers, a series of tests was carried out in male and female patients. METHODS: Chronic pain occurrence and sensory phenotype profile were assessed in 30 patients (20 male: 10 AMN, 1 cAMN, 1 cALD, 8 AD; and 10 female). A set of instruments assessed the intensity, quality and extent of pain, while a battery of quantitative sensory testing (QST) procedures examined the functional status of Aß and Aδ fibers. Principal component analysis and hierarchical clustering with sensory responses input were used to identify distinct clusters. RESULTS: Nearly half of the subjects reported pain, with a high prevalence in females and male AMN patients. No sex differences in pain dimensions were found. The sensory responses were heterogeneous, differing among the clinical variants and between genders. Male AMN/cAMN/cALD patients showed the worst impairment. Aß and Aδ fibers were affected in males and females, but Aß fibers appeared undamaged in females when tactile sensitivity was tested. Abnormal responses were localized in the lower body district, according to the dying-back pattern of the neuropathy. Cluster analysis showed discrete clusters for each function examined, with well-interpretable sensory and clinical phenotypes. CONCLUSION: The study of pain and of the sensory profile appears to indicate a difference in the mechanisms underlying the AMN/cAMN/cALD and AD clinical forms and in the treatment of the respective generated pain types.

A novel human pain insensitivity disorder caused by a point mutation in ZFHX2.

Chronic pain is a major global public health issue causing a severe impact on both the quality of life for sufferers and the wider economy. Despite the significant clinical burden, little progress has been made in terms of therapeutic development. A unique approach to identifying new human-validated analgesic drug targets is to study rare families with inherited pain insensitivity. Here we have analysed an otherwise normal family where six affected individuals display a pain insensitive phenotype that is characterized by hyposensitivity to noxious heat and painless bone fractures. This autosomal dominant disorder is found in three generations and is not associated with a peripheral neuropathy. A novel point mutation in ZFHX2, encoding a putative transcription factor expressed in small diameter sensory neurons, was identified by whole exome sequencing that segregates with the pain insensitivity. The mutation is predicted to change an evolutionarily highly conserved arginine residue 1913 to a lysine within a homeodomain. Bacterial artificial chromosome (BAC) transgenic mice bearing the orthologous murine p.R1907K mutation, as well as Zfhx2 null mutant mice, have significant deficits in pain sensitivity. Gene expression analyses in dorsal root ganglia from mutant and wild-type mice show altered expression of genes implicated in peripheral pain mechanisms. The ZFHX2 variant and downstream regulated genes associated with a human pain-insensitive phenotype are therefore potential novel targets for the development of new analgesic drugs.awx326media15680039660001.

Menopause affects pain depending on pain type and characteristics.

OBJECTIVE: Women are more affected than men by many chronic pain conditions, suggesting the effect of sex-related mechanisms in their occurrence. The role of gonadal hormones has been studied but with contrasting results depending on the pain syndrome, reproductive status, and hormone considered. The aim of the present study was to evaluate the pain changes related to the menopausal transition period. METHODS: In this observational study, postmenopausal women were asked to evaluate the presence of pain in their life during the premenopausal and postmenopausal periods and its modification with menopause. RESULTS: One hundred one women were enrolled and completed questionnaires on their sociodemographic status, pain characteristics, and evolution. The most common pain syndromes were headache (38%), osteoarticular pain (31%), and cervical/lumbar pain (21%). Pain was present before menopause in 66 women, ceased with menopause in 17, and started after menopause in 18. Data were used for cluster analysis, which allowed the division of participants into four groups. In the first, all women experienced headaches that disappeared or improved with menopause. The second group included osteoarticular pain; the pain improved in half of these women and remained stable in the other half. The third group had cervical/lumbar pain, which disappeared or improved with menopause in all. The fourth group presented different kinds of moderate pain, which worsened in all. CONCLUSIONS: The present study provides preliminary data suggesting that menopause can affect pain depending on the painful condition experienced by the woman. This underlines the different interactions of menopause-related events with body structures involved in pain.

Lymphocyte TRPV 1-4 gene expression and MIF blood levels in a young girl clinically diagnosed with HSAN IV.

OBJECTIVE: Patients with congenital insensitivity to pain are unable to sense pain and temperature. They undergo many injuries, inflammatory state, and infections. Various mutations in the neurotrophic tyrosine kinase receptor gene have been implicated in this disorder. We measured the leukocyte expression of transient receptor potential vanilloid (TRPV) 1-4 genes and the blood macrophage migration inhibitory factor (MIF) concentration in a young girl clinically diagnosed with congenital insensitivity to pain. The investigation may help to define the interplay between nerve growth factor and TRPV 1-4 channels and between these sensors and MIF in this disease, and in broader terms in nociception. METHODS: TRPV 1-4 gene expression (real-time polymerase chain reaction) and MIF concentration (enzyme-linked immunosorbent assay) were determined in the blood of the girl, her family, and control participants. Statistical analysis of gene expression was carried out between samples and controls with a mathematical model based on the correction for exact polymerase chain reaction efficiencies, and the mean crossing point deviation between samples and controls. RESULTS: The TRPV 1--4 gene expression rates did not significantly differ from the values found in the control group. TRPV1 was almost doubly upregulated. MIF levels were much higher than the reference value. DISCUSSION: The high increase in the MIF concentration (likely due to the chronic or recurrent inflammatory state) may have contributed to the normal expression of TRPV 1-4 and to the relative upregulation of TRPV1. The role of this cytokine on the expression of these genes deserves further investigation.

Hormone replacement therapy in morphine-induced hypogonadic male chronic pain patients.

BACKGROUND: In male patients suffering from chronic pain, opioid administration induces severe hypogonadism, leading to impaired physical and psychological conditions such as fatigue, anaemia and depression. Hormone replacement therapy is rarely considered for these hypogonadic patients, notwithstanding the various pharmacological solutions available. METHODS: To treat hypogonadism and to evaluate the consequent endocrine, physical and psychological changes in male chronic pain patients treated with morphine (epidural route), we tested the administration of testosterone via a gel formulation for one year. Hormonal (total testosterone, estradiol, free testosterone, DHT, cortisol), pain (VAS and other pain questionnaires), andrological (Ageing Males' Symptoms Scale-AMS) and psychological (POMS, CES-D and SF-36) parameters were evaluated at baseline (T0) and after 3, 6 and 12 months (T3, T6, T12 respectively). RESULTS: The daily administration of testosterone increased total and free testosterone and DHT at T3, and the levels remained high until T12. Pain rating indexes (QUID) progressively improved from T3 to T12 while the other pain parameters (VAS, Area%) remained unchanged. The AMS sexual dimension and SF-36 Mental Index displayed a significant improvement over time. CONCLUSIONS: In conclusion, our results suggest that a constant, long-term supply of testosterone can induce a general improvement of the male chronic pain patient's quality of life, an important clinical aspect of pain management.

Julia's placebo effect.

Placebo analgesia is the occurrence of an analgesic drug effect without drugs. The response is learned through conditioning and mediated by expectancy. It lies on the up-regulation of the pain-modulating areas and the down-regulation of the pain-encoding regions. A further mechanism is the retrieval of the brain circuit activity previously excited by drugs. We describe the case of an infant affected by a tracheal agenesis who underwent a series of operative and diagnostic bronchoscopies for which she received midazolam and fentanyl. After 61 procedures the infant showed a somatosensory response which in our interpretation reflected a placebo effect. Ontogenetic considerations and specific observations indicate that the infant had the appropriate competences in her learning and memory systems and nociceptive and antinociceptive circuits for the placebo effect to take place. Generalizing, the introduction of placebo manipulation in infant pain management may be taken into consideration; its approach through observational and experimental studies is the preliminary target.

Endocrine consequences of opioid therapy.

Gonadal hormones are known to be affected by morphine and other opioids. In this paper, we summarize data collected in recent years which clearly indicate that the opioid-induced effects on steroid hormones depend on the opioid used and in some cases on the sex of the subject. Indeed morphine is able to reduce hormones like testosterone and cortisol in both male and female subjects in just a few hours, probably acting directly on peripheral glands. These depressant effects of morphine on hormones are also present in the treatment of surgical pain and are quickly reversible once opioid administration is suspended. Similar actions were also found to occur in experimental animals and in vitro in glial cells, further confirming the morphine-induced reduction of testosterone cell content. Testosterone and its metabolites are well known substances involved in the development and maintenance of the brain and all body structures. Thus when treating pain with opioids, their effects on hypothalamo-pituitary-gonadal and hypothalamo-pituitary-adrenal-related hormones must be considered and, where possible, hormone replacement therapy should be started.

Quantitative Real-Time PCR detection of TRPV1-4 gene expression in human leukocytes from healthy and hyposensitive subjects.

BACKGROUND: Besides functioning as chemosensors for a broad range of endogenous and synthetic ligands, transient receptor potential vanilloid (TRPV) 1-4 channels have also been related to capsaicin (TRPV1), pain, and thermal stimuli perception, and itching sensation (TRPV1-4). While the expression of the TRPV1-4 genes has been adequately proved in skin, sensory fibres and keratinocytes, less is known about TRPV3 and TRPV4 expression in human blood cells. RESULTS: To study the gene expression of TRPV1-4 genes in human leukocytes, a quantitative Real-Time PCR (qRT-PCR) method, based on the calculation of their relative expression, has been developed and validated. The four commonly used house-keeping genes (HKGs), beta-Actin (Act-B), glyceraldehyde-3P-dehydrogenase (GAPDH), hypoxanthine ribosyltransferase (HPRT1), and cyclophilin B (hCyPB), were tested for the stability of their expression in several human leukocyte samples, and used in the normalization procedure to determine the mRNA levels of the TRPV 1-4 genes in 30 healthy subjects. cDNAs belonging to all the TRPV1-4 genes were detected in leukocytes but the genes appear to be expressed at different levels. Our analysis did not show significant sex differences in TRPV1-4 cDNA levels in the 30 healthy subjects. The same qRT-PCR assay was used to compare TRPV1-4 expression between healthy controls and patients hyposensitive to capsaicin, pain and thermal stimuli: an almost doubled up-regulation of the TRPV1 gene was found in the pathological subjects. CONCLUSION: The qRT-PCR assay developed and tested in this study allowed us to determine the relative expression of TRPV1-4 genes in human leukocytes: TRPV3 is the least expressed gene of this pool, followed by TRPV4, TRPV1 and TRPV2. The comparison of TRPV1-4 gene expression between two groups of healthy and hyposensitive subjects highlighted the evident up-regulation of TRPV1, which was almost doubly expressed (1.9x normalized fold induction) in the latter group. All the four house-keeping genes tested in this work (Act-B, GAPDH, hCyPB, HPRT1) were classified as optimal controls and showed a constant expression in human leukocytes samples. We recommend the use of these genes in similar qRT-PCR studies on human blood cells.

Sensory phenotype assessment in a young girl affected by congenital insensitivity to pain (CIPA).

Sensory phenotype was assessed in a young girl affected by congenital insensitivity to pain (CIPA) scheduled for an open surgical drainage. The sensory profile showed that only the Abeta fibers were functioning normally, whereas Adelta and C fibers did not respond to nociceptive stimuli. On the basis of these findings and the results of cardiovascular reflexes, she was submitted to abscess incision and debridement under midazolam sedation alone. She did not report pain or other discomfort during surgery. The sensory (and sympathetic) assessment may have a high potential value in planning anesthesia and analgesia in children with CIPA. This psychophysical procedure could be introduced as standard component of clinical evaluation before surgery.

Cross-sex hormone administration changes pain in transsexual women and men.

Chronic pain is gender-related, since there is a clear predominance of one sex with respect to the other in most pain syndromes. Gonadal hormones are known to affect the occurrence and incidence of pain. Transsexuals receive cross-sex hormones to develop and maintain somatic characteristics of the opposite sex: male to female transsexuals (MtF) are administered estrogens and anti-androgens, while female to male transsexuals (FtM) are administered androgens. Hence, these subjects represent a model to study the relationship between sex hormones and pain. Questionnaires dealing with sociodemographic data and pain (occurrence, frequency, duration, intensity, location and associated symptoms) were administered to both MtF and FtM transsexuals under hormone treatment for sex reassignment for at least 1 year. Forty-seven MtF and 26 FtM completed the questionnaires. Fourteen of the 47 MtF (29.8%) reported painful conditions, which in 11 subjects were not present before the beginning of hormone treatment. Pain consisted mainly of headaches and breast and musculoskeletal pain. Five subjects suffered from more than one pain condition. Sixteen of the 26 FtM (61.5%) reported pain. In 11 subjects, the pain was present before the beginning of hormone intake, and in 6 of them it improved after testosterone administration. These data suggest that marked changes in sex hormones affect the occurrence of pain in a high percentage of humans but not in all of them. Whether these effects are due to peripheral or central actions of sex steroids is unknown.

Severe withdrawal syndrome in three newborns subjected to continuous opioid infusion and seizure activity dependent on brain hypoxia--ischemia. A possible link.

BACKGROUND: The aim of this investigation was to verify whether brain hypoxia represented a risk factor for the occurrence and severity of opioid abstinence syndrome. METHODS: Three newborns who manifested seizure activity as a result of hypoxia, focal brain ischemia, and hypoxia and sepsis, respectively, were compared with 17 neonates who suffered from hypoxia without developing seizure activity. RESULTS: The first three neonates suffered a severe withdrawal syndrome (a rating on the neonatal abstinence score>17), the others did not. CONCLUSIONS: It is hypothesized that brain hypoxia facilitated the occurrence and severity of the withdrawal syndrome because some key neurochemical processes (such as N-methyl-D-aspartate activation, protein kinase C activation and nitric oxide production) are common to both phenomena.

Removal of an unexpected tracheal foreign body after five months.

Foreign body aspiration can produce serious pulmonary diseases. Timely diagnosis and appropriate treatment is important to prevent long-term complications in affected children. We report the case of a 15-month-old child with a 5-month history of regurgitation, vomiting, recurrent tracheobronchitis, and pneumonia. The diagnosis was gastroesophageal reflux. The laryngotracheal endoscopy revealed a rabbit vertebra partially obstructing the airway at the level of the cricoid cartilage. With a rigid bronchoscope and forceps equipped with a telescope, it was possible to disengage and extract the foreign body. Six months later endoscopic control revealed no residual alterations in the larynx and trachea.

The pain locus of control orientation in a healthy sample of the Italian population: sociodemographic modulating factors.

We studied the pain locus of control orientation of the Italian population and the possible influence of the ethnocultural background and sociodemographic characteristics on this attributional style. An Italian version of the Pain Locus of Control (PLOC-It) scale was administered to 144 healthy subjects, divided into two ethnocultural areas (North vs South) and stratified by age (per decade 21-60), gender (female and male) and educational level (3). The Powerful Other subscale had the highest mean score, followed by the Internality and Chance subscales. ANOVA revealed significant effects of ethnocultural area and educational level on Internality (F = 724, p < 0.001; F = 5.05, p < 0.05) and of age on Chance (F = 13.6, p < 0.001). There was a significant three-way interaction between area, gender and educational level on Powerful Other (F = 3.67, p < 0.05). Further studies should be performed in populations of various countries to better identify the attributional styles related to the different cultures and the absolute sociodemographic determinants of the pain locus of control orientation.