Things Able to Treat Pain.

Chronic pain is a medical condition that affects a considerable number of people of all ages [...].

Age and training intensity differently affect male runners' endocrine and sexual parameters.

Physical activity is widely recognized to improve health and its inclusion in daily life at all ages is highly recommended. Gonadal hormones are known to be affected by physical activity. The exercise-induced effects on male runners of different ages were investigated by dividing 31 runners by age (Young, Y, 30-55 years; Old, O, 56-70 years) and amount of training (Light, L, <50 km/week; Heavy, H, 50 or more km/week). To test the somatic, sexual, and psychological health aspects, the Aging Male's Symptoms Scale (AMS) and the International Index of Erectile Function-6 (IIEF-6) questionnaires were administered and blood samples were drawn for adrenocorticotropic hormone, testosterone (Total-TT), free testosterone (Free-T), cortisol (C), dihydrotestosterone (DHT), estradiol, and sex hormone-binding globulin determinations. Clinical evaluations and questionnaire results showed the presence in all groups of some subclinical symptoms and "Light" dysfunctions. TT in the old-heavy (OH) group was significantly lower than in the OL group (2.38 ± 0.18 ng/mL vs. 3.36 ± 0.44 ng/ml, P = 0.05). The TT/DHT ratio was significantly higher in YH than in OH (3.64 ± 0.16 vs. 2.92 ± 0.23, P < 0.05). TT was positively correlated with AMS sexual subscale and negatively correlated with IIEF-6. Physical activity can significantly affect andrological health and testosterone levels in runners at all ages. Thus, due to the important testosterone-mediated vital functions in men, the evaluation of these parameters would be indicated in old as well as in young subjects.

Calceolarioside A, a Phenylpropanoid Glycoside from Calceolaria spp., Displays Antinociceptive and Anti-Inflammatory Properties.

Phenylpropanoid glycosides are a class of natural substances of plant origin with interesting biological activities and pharmacological properties. This study reports the antinociceptive and anti-inflammatory effects of calceolarioside A, a phenylpropanoid glycoside previously isolated from various Calceolaria species. In models of acute nociception induced by thermal stimuli, such as the hot plate and tail flick test, calceolarioside administered at doses of 1, 5, and 10 µg in the left cerebral ventricles did not modify the behavioral response of mice. In an inflammatory based persistent pain model as the formalin test, calceolarioside A at the high dose tested (100 µg/paw) reduced the licking activity induced by formalin by 35% in the first phase and by 75% in the second phase of the test. In carrageenan-induced thermal hyperalgesia, calceolarioside A (50 and 100 µg/paw) was able to significantly reverse thermal hyperalgesia induced by carrageenan. The anti-inflammatory activity of calceolarioside A was then assessed using the zymosan-induced paw edema model. Calceolarioside A (50 and 100 µg/paw) induced a significant reduction in the edema from 1 to 4 h after zymosan administration. Measuring IL-6, TNFα, and IL-1ß pro-inflammatory cytokines released from LPS-stimulated THP-1 cells, calceolarioside A in a concentration-dependent manner reduced the release of these cytokines from THP-1 cells. Taken together, our results highlight, for the first time, the potential and selective anti-inflammatory properties of this natural-derived compound, prompting its rationale use for further investigations.

Superior Properties of N-Acetylcysteine Ethyl Ester over N-Acetyl Cysteine to Prevent Retinal Pigment Epithelial Cells Oxidative Damage.

Oxidative stress plays a key role in the pathophysiology of retinal diseases, including age-related macular degeneration (AMD) and diabetic retinopathy, which are the major causes of irreversible blindness in developed countries. An excess of reactive oxygen species (ROS) can directly cause functional and morphological impairments in retinal pigment epithelium (RPE), endothelial cells, and retinal ganglion cells. Antioxidants may represent a preventive/therapeutic strategy and reduce the risk of progression of AMD. Among antioxidants, N-acetyl-L-cysteine (NAC) is widely studied and has been proposed to have therapeutic benefit in treating AMD by mitigating oxidative damage in RPE. Here, we demonstrate that N-acetyl-L-cysteine ethyl ester (NACET), a lipophilic cell-permeable cysteine derivative, increases the viability in oxidative stressed RPE cells more efficiently than NAC by reacting directly and more rapidly with oxidizing agents, and that NACET, but not NAC, pretreatment predisposes RPE cells to oxidative stress resistance and increases the intracellular reduced glutathione (GSH) pool available to act as natural antioxidant defense. Moreover, we demonstrate the ability of NACET to increase GSH levels in rats' eyes after oral administration. In conclusion, even if experiments in AMD animal models are still needed, our data suggest that NACET may play an important role in preventing and treating retinal diseases associated with oxidative stress, and may represent a valid and more efficient alternative to NAC in therapeutic protocols in which NAC has already shown promising results.

Thermogenic flux induced by lignoceric acid in peroxisomes isolated from HepG2 cells and from X-adrenoleukodystrophy and control fibroblasts.

This work analyzes the thermogenic flux induced by the very long-chain fatty acid (VLCFA) lignoceric acid (C24:0) in isolated peroxisomes. Specific metabolic alterations of peroxisomes are related to a variety of disorders, the most frequent one being the neurodegenerative inherited disease X-linked adrenoleukodystrophy (X-ALD). A peroxisomal transport protein is mutated in this disorder. Due to reduced catabolism and enhanced fatty acid (FA) elongation, VLCFA accumulates in plasma and in all tissues, contributing to the clinical manifestations of this disorder. During peroxisomal metabolism, heat is produced but it is considered lost. Instead, it is a form of energy that could play a role in molecular mechanisms of this pathology and other neurodegenerative disorders. The thermogenic flux induced by lignoceric acid (C24:0) was estimated by isothermal titration calorimetry in peroxisomes isolated from HepG2 cells and from fibroblasts obtained from patients with X-ALD and healthy subjects. Heat flux induced by lignoceric acid in HepG2 peroxisomes was exothermic, indicating normal peroxisomal metabolism. In X-ALD peroxisomes the heat flux was endothermic, indicating the requirement of heat/energy, possibly for cellular metabolism. In fibroblasts from healthy subjects, the effect was less pronounced than in HepG2, a kind of cell known to have greater FA metabolism than fibroblasts. Our hypothesis is that heat is not lost but it could act as an activator, for example on the heat-sensitive pathway related to TRVP2 receptors. To investigate this hypothesis we focused on peroxisomal metabolism, considering that impaired heat generation could contribute to the development of peroxisomal neurodegenerative disorders.

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.

Effects of Intracerebroventricular and Intra-Arcuate Nucleus Injection of Ghrelin on Pain Behavioral Responses and Met-Enkephalin and ß-Endorphin Concentrations in the Periaqueductal Gray Area in Rats.

Ghrelin is an endogenous ligand for orphan growth hormone secretagogue receptors. Ghrelin receptors have been found in central nervous system (CNS) areas responsible for pain modulation and transmission. This study investigated the effects of intracerebroventricular (ICV) and intra-arcuate nucleus (ARC) injection of ghrelin on pain behavioral responses and levels of ß-endorphin (ß-EP) and met-enkephalin (MENK) in the periaqueductal gray area (PAG) during the formalin test in rats. Thirty-five male rats were studied in five groups. Ghrelin was injected into the left lateral ventricle (ICV, 5 µL) or into the ARC (1 µL). After 15 min, formalin (2.5%) was subcutaneously injected into the left hind paw. Behavioral nociceptive scores were recorded for 60 min. MENK and ß-EP were collected by microdialysis in the PAG and determined by high-performance liquid chromatography (HPLC). ICV and ARC injection of ghrelin significantly reduced pain in all phases of the formalin test (p < 0.001). Dialysate concentrations of MENK and ß-EP in the PAG increased in all the phases (p < 0.01). In conclusion, the present study shows that the ARC nucleus and the endogenous opioid system are involved in ghrelin-induced pain modulation.

Determination of protein thiolation index (PTI) as a biomarker of oxidative stress in human serum.

We have introduced protein thiolation index (PTI), i.e. the molar ratio of the sum of all low molecular mass thiols bound to plasma proteins to protein free cysteinyl residues, as a sensitive biomarker of oxidative stress. According to the original procedure its determination requires a rapid separation of plasma and a specific treatment of samples to stabilize thiols. Here we demonstrate that samples can be collected without use of any anticoagulant to prevent blood clotting and without any stabilization of thiols too. This simplification of the determination of PTI makes its analysis more feasible also in routine clinical laboratories.

The influence of altitude hypoxia on uroflowmetry parameters in women.

There is scientific evidence to suggest a correlation between hypoxia and the physiology of micturition. During a Himalayan Scientific and Mountaineering Expedition, we performed tests to investigate the functional interactions between altitude hypoxia and uroflowmetry parameters in women. The tests were carried out in seven women (36.3 ± 7.1 yr) from normoxic [1,340 meters above sea level (m a.s.l.)] to hypoxic conditions (up to 5,050 m a.s.l.) and during the return descent. The following measures were determined: uroflowmetry parameters and saturation of peripheral oxygen (SpO2 ). As expected, SpO2 decreased from 97.7 to 77.8% with increasing altitude. Micturition flow time, flow volume, and voiding time increased with altitude (P < 0.04 for all), indicating a negative correlation with SpO2 In conclusion, in young adult women, micturition physiological parameters were affected during adaptation to hypoxia; the correlation with SpO2 strongly suggests a role of hypoxia in these changes. These data could help to support the design of new strategies for both prevention and medical treatment. An example of the latter might be hyperbaric oxygen therapy, which in some studies has proved able to reduce the symptoms in patients with hypoxic bladder.

Effects of neonatal pain, stress and their interrelation on pain sensitivity in later life in male rats.

Neonatal pain and stress induce long-term changes in pain sensitivity. Therefore their interrelation is a topical subject of clinical and basic research. The present study investigated the effects of inflammatory peripheral pain and stress of maternal deprivation (MD)-isolation in 1-2- and 7-8-day-old Wistar rats (P1,2 and P7,8 respectively, ages comparable to preterm and full-term human babies) on basal pain and pain sensitivity in conditions of inflammatory pain (formalin test) during adolescence. The neonatal impacts were: pain (formalin injection, FOR in the paw), stress (a short 60-min MD), or pain+stress combination (FOR+MD), and appropriate controls. We found that stress of short-term maternal deprivation-isolation and inflammatory pain on P1,2 and P7,8 significantly increased the vulnerability of the nociceptive system to inflammatory pain. Maternal deprivation-isolation on P1,2 as compared with a similar impact on P7,8 had a greater effect on pain sensitivity of the adolescent rats, but the influence of early pain was independent of the injury age. Only adolescent rats with an early combination of pain and maternal deprivation-isolation showed hypoalgesia in the hot plate (HP) test. However licking duration (reflecting pain sensitivity) in these rats did not exceed licking duration in animals exposed only to maternal deprivation-isolation or pain. This study adds new data to the growing body of work demonstrating that early noxious impacts have long-term consequences for the functional activity of the nociceptive system. Our new findings may help to understand the impact of pain and maternal separation in the neonatal intensive care unit.

Dynamic Mechanical Allodynia--One Clinical Sign, Several Mechanisms: Five Illustrative Cases.

Pain evoked by tangential movement across the skin is usually defined as dynamic mechanical allodynia (DMA). Some patients complain of DMA as troublesome as spontaneous pain and refer a marked interfering with activities of daily living and sleep. Pathophysiology of DMA is complex and can be related to several mechanisms, both nociceptive and neuropathic. Five exemplificative clinical cases of DMA are presented, each associated to a possible specific mechanism: injured skin DMA, peri-injured skin DMA, far injury DMA, nerve-confined DMA and fear DMA (pseudo allodynia). The identification of these subcategories of DMA can stimulate further studies aimed at evaluating the usefulness of a mechanism-based therapy for the different clinical forms of DMA.

Perinatal 17α-ethinylestradiol exposure affects formalin-induced responses in middle-aged male (but not female) rats.

17α-Ethinylestradiol (EE), the main component of the contraceptive pill, is a synthetic estrogen found in rivers of the United States and Europe as an environmental contaminant. It is one of the most studied xenoestrogens due to its possible effect on the reproductive system. In the present study we evaluated the modulation of pain responses induced by formalin injection (licking, flexing, paw-jerk) in 8-month-old male and female offspring of female rats treated with two different doses of EE (4ng/kg/day or 400ng/kg/day) during pregnancy and lactation. Spontaneous behaviors and gonadal hormone levels were also determined. Both concentrations of EE induced an increase of pain behaviors in males only, i.e. higher flexing and licking of the formalin-injected paw than in OIL-exposed rats, during the second, inflammatory, phase of the formalin test. Grooming duration was increased by EE exposure in both males and females. Prenatal EE exposure (both concentrations) decreased estradiol plasma levels in the formalin-injected females but not in the males. These results underline the possibility that exposure to an environmental contaminant during the critical period of development can affect neural processes (such as those involved in pain modulation) during adulthood, indicating long-term changes in brain circuitry. However, such changes may be different in males and females.

A Personalized Mediterranean Diet Improves Pain and Quality of Life in Patients with Fibromyalgia.

INTRODUCTION: Fibromyalgia is a form of chronic pain that affects a large number of women. It can start at any age and last a lifetime, with no cure. The Mediterranean diet is said to have an anti-inflammatory effect. Therefore, this study was conducted to investigate possible beneficial effects of a personalized Mediterranean diet in patients with fibromyalgia. METHODS: Outpatients with fibromyalgia were recruited and invited to participate in the study, including clinical, nutritional, and dietary assessments. Patients received a personalized Mediterranean diet (DIET group) or a general balanced diet (NODIET group) to be followed for 8 weeks. All tests were carried out at baseline and repeated after 4 and 8 weeks. RESULTS: In total, 100 subjects were included, 84 of whom completed the study. Most of the patients showed incorrect habits in terms of food choices, timing of meals and composition of nutrients. The DIET group showed an improvement in most of the fibromyalgia parameters, including the disability scores, fatigue, and anxiety. CONCLUSIONS: The habit of eating inflammatory foods and/or eating meals with the wrong nutritional content would increase the negative status of patients with fibromyalgia. With this study, we confirm that proper attention to feeding habits would improve the quality of life of such patients.

Pain and thyroid hormones.

The role of endocrine systems in chronic pain mechanisms is slowly getting increasing experimental and clinical consideration. Many painful conditions appear to be directly and/or indirectly induced, reduced or, in some cases, modulated by hormones. We have done much work in trying to understand the relationship between hormones and pain, with particular attention to the hypothalamus-pituitary-gonadal axis. To expand our knowledge of this field, we have directed our attention to another axis, the hypothalamus-pituitary-thyroid (HPT). The literature on thyroid functions is vast but very few studies have focused on the HPT axis and pain. The few available data are considered in the present review to stimulate interest in the possible interactions between the HPT axis and pain.

Testosterone-induced effects on lipids and inflammation.

Chronic pain has to be considered in all respects a debilitating disease and 10-20% of the world's adult population is affected by this disease. In the most general terms, pain is symptomatic of some form of dysfunction and (often) the resulting inflammatory processes in the body. In the study of pain, great attention has been paid to the possible involvement of gonadal hormones, especially in recent years. In particular, testosterone, the main androgen, is thought to play a beneficial, protective role in the body. Other important elements to be related to pain, inflammation, and hormones are lipids, heterogenic molecules whose altered metabolism is often accompanied by the release of interleukins, and lipid-derived proinflammatory mediators. Here we report data on interactions often not considered in chronic pain mechanisms.

Inflammatory pain and corticosterone response in infant rats: effect of 5-HT1A agonist buspirone prior to gestational stress.

Our researches have shown that gestational stress causes exacerbation of inflammatory pain in the offspring; the maternal 5-HT1A agonist buspirone before the stress prevents the adverse effect. The serotonergic system and hypothalamo-pituitary-adrenal (HPA) axis are closely interrelated. However, interrelations between inflammatory pain and the HPA axis during the hyporeactive period of the latter have not been studied. The present research demonstrates that formalin-induced pain causes a gradual and prolonged increase in plasma corticosterone level in 7-day-old male rats; twenty-four hours after injection of formalin, the basal corticosterone level still exceeds the initial basal corticosterone value. Chronic treatments of rat dams with buspirone before restraint stress during gestation normalize in the offspring pain-like behavior and induce during the acute phase in the formalin test the stronger corticosterone increase as compared to the stress hormonal elevation in animals with other prenatal treatments. Negative correlation between plasma corticosterone level and the number of flexes+shakes is revealed in buspirone+stress rats. The new data enhance the idea about relativity of the HPA axis hyporeactive period and suggest that maternal buspirone prior to stress during gestation may enhance an adaptive mechanism of the inflammatory nociceptive system in the infant male offspring through activation of the HPA axis peripheral link.

Allodynic skin in post-herpetic neuralgia: histological correlates.

Most post-herpetic neuralgia (PHN) patients suffer from tactile allodynia (pain evoked by lightly touching the skin) and it is frequently the dominant clinical manifestation. The pathophysiology of tactile allodynia in PHN patients is poorly understood and this is one of the major limits to the development of appropriate therapies. Epidermal nerve fibres (ENFs) are free nerve endings of small-diameter A-delta and C primary afferents, which can easily be assessed by neurodiagnostic skin biopsy (NSB). The aim of this study was to establish the correlation between the residual epidermal innervation of the allodynic skin and the intensity of tactile allodynia in that area. Twenty-five patients (13 males and 12 females) with PHN were enrolled. Eighteen patients had PHN in the thoracic dermatome, four in the cervical, two in the trigeminal and one in the lumbar. The severity of allodynia evoked by a paintbrush was graded according to an eleven-point numerical scale. A skin biopsy was obtained from the maximal allodynia area and from the contralateral skin. Nerve fibres were labelled with indirect immunofluorescence. Results showed that epidermal innervation was lower in the allodynic skin than in the contralateral skin, although there was great variability among patients. There was no correlation between severity of allodynia and epidermal innervation of the PHN skin. In conclusion, the present study further indicates peripheral nervous system involvement in PHN but does not support a direct correlation between epidermal innervation changes and tactile allodynia.

Impact of testosterone on body fat composition.

An excessive food supply has resulted in an increasing prevalence of overweight and obesity, conditions accompanied by serious health problems. Several studies have confirmed the significant inverse correlation between testosterone and obesity. Indeed after decades of intense controversy, a consensus has emerged that androgens are important regulators of fat mass and distribution in mammals and that androgen status affects cellularity in vivo. The high correlation of testosterone levels with body composition and its contribution to the balance of lipid metabolism are also suggested by the fact that testosterone lowering is associated with important clinical disorders such as dyslipidemia, atherosclerosis, cardiovascular diseases, metabolic syndrome and diabetes. In contrast, testosterone supplementation therapy in hypogonadic men has been shown to improve the lipid profile by lowering cholesterol, blood sugar and insulin resistance. Leptin, ghrelin and adiponectin are some of the substances related to feeding as well as androgen regulation. Thus, complex and delicate mechanisms appear to link androgens with various tissues (liver, adipose tissue, muscles, coronary arteries and heart) and the subtle alteration of some of these interactions might be the cause of correlated diseases. This review underlines some aspects regarding the high correlations between testosterone physiology and body fat composition.

Food addiction assessment in a nonclinical sample of the Italian population.

OBJECTIVE: Discussion about the potential addictive role of certain types of food and their link with obesity has recently increased. Researchers have developed instruments to specifically assess food addiction (FA). The aim of this pilot study was to investigate the prevalence of food addiction in a nonclinical sample of the Italian population. METHODS: All participants (n = 148: 46 males, 102 females) completed the Yale Food Addiction Scale 2.0 (YFAS 2.0) and provided self-reported measures and demographic information. They were divided into three age groups. RESULTS: The prevalence of FA was 15.5% of our sample (82.6% of the subjects diagnosed with FA were female). The FA symptoms mean was 1.90 (SD = 2.87). In both sexes, participants aged 18-30 had the highest diagnosis of FA, with 52.1% of all FA subjects being females aged 18-30. According to the Body Mass Index (BMI), all the males diagnosed with FA were overweight or obese, as were most (63.2%) of the FA females. CONCLUSIONS: Future food education policies could consider FA assessment together with that of other eating disorders, even among nonclinical subjects in order to anticipate diagnosis and improve treatment.

Food-Specific IgG4 Antibody-Guided Exclusion Diet Improves Conditions of Patients with Chronic Pain.

INTRODUCTION: Chronic pain is related to gastrointestinal (GI) functions because food components affect inflammation and pain through their action on the GI immune and/or neural system and because many analgesics interact with the gut to alter its structure and function. Immunoglobulin G4 (IgG4) are food-specific antibodies resulting from exposure of the gut immune system to nutrients. High IgG4 levels have been found to be associated with inflammation. METHODS: IgG4 were determined (both with the rapid test and enzyme-linked immunosorbent assay, ELISA) in men and women outpatients with chronic pain. All subjects were asked to exclude for 4 weeks all foods to which they had high blood levels of IgG4 antibodies. Pain and quality of life questionnaires were administered before (visit 1) and after (visit 2) the personalized exclusion diet period. Visual analogue scale (VAS), Italian Pain Questionnaire (QUID) and Margolis (MA) questionnaires were administered to determine pain intensity, pain features and pain extent, while Short Form Health Survey (SF-36) and Profile of Mood States (POMS) were used to test the quality of life and mood state. The nutritional status was evaluated in all subjects. Subject groups were women of reproductive age (pre-MW), women in menopause for at least 1 year (MW) and men. RESULTS: Fifty-four subjects with chronic pain (n = 12 neuropathic, n = 14 diffuse pain, n = 11 headache, n = 17 low back pain) completed the two visits and the 1-month exclusion diet. At visit 1, 47 (87%) subjects showed medium/high levels of IgG4 to at least one food. The foods showing the highest IgG4 values were eggs, dairy products, cereals and dried fruit. At visit 2, IgG4 levels were decreased, increased or unchanged. In all groups, the 4-week exclusion diet resulted in a significant reduction in all pain measures and an improvement of quality of life parameters. In particular, at visit 2, the VAS score determined in the morning decreased by more than 50%. CONCLUSIONS: A food elimination diet based on IgG4 antibody levels may be effective in reducing pain and improving quality of life in patients with chronic pain.