Identification of Potential Visceral Pain Biomarkers in Colon Exudates from Mice with Experimental Colitis: An Exploratory In Vitro Study

Chronic visceral pain (CVP) is extremely difficult to diagnose, and available analgesic treatment options are quite limited. Identifying the proteins secreted from the colonic nociceptors, or their neighbor cells within the tube walls, in the context of disorders that course with visceral pain, might be useful to decipher the mechanism involved in the establishment of CVP. Addressing this question in human with gastrointestinal disorders entails multiple difficulties, as there is not a clear classification of disease severity, and colonic secretion is not easy to manage. We propose using of a murine model of colitis to identify new algesic molecules and pathways that could be explored as pain biomarkers or analgesia targets. Descending colons from naïve and colitis mice with visceral hyperalgesia were excised and maintained ex vivo. The proteins secreted in the perfusion fluid before and during acute noxious distension were evaluated using high-resolution mass spectrometry (MS). Haptoglobin (Hp), PZD and LIM domain protein 3 (Pdlim3), NADP-dependent malic enzyme (Me1), and Apolipoprotein A-I (Apoa1) were increased during visceral insult, whilst Triosephosphate isomerase (Tpi1), Glucose-6-phosphate isomerase (Gpi1), Alpha-enolase (Eno1), and Isoform 2 of Tropomyosin alpha-1 chain (Tpm1) were decreased. Most identified proteins have been described in the context of different chronic pain conditions and, according to gene ontology analysis, they are also involved in diverse biological processes of relevance. Thus, animal models that mimic human conditions in combination with unbiased omics approaches will ultimately help to identify new pathophysiological mechanisms underlying pain that might be useful in diagnosing and treating pain. Perspective: Our study utilizes an unbiased proteomic approach to determine, first, the clinical relevance of a murine model of colitis and, second, to identify novel molecules/pathways involved in nociception that would be potential biomarkers or targets for chronic visceral pain

Neurophysiological mechanisms of chiropractic spinal manipulation for spine pain

Abstract Together, neck pain and back pain are the first cause of disability worldwide, accounting for more than 10% of the total years lived with disability. In this context, chiropractic care provides a safe and effective option for the management of a large proportion of these patients. Chiropractic is a healthcare profession mainly focused on the spine and the treatment of spinal disorders, including spine pain. Basic studies have examined the influence of chiropractic spinal manipulation on a variety of peripheral, spinal, and supraspinal mechanisms involved in spine pain. While spinal cord mechanisms of pain inhibition contribute at least partly to the pain-relieving effects of chiropractic treatments, the evidence is weaker regarding peripheral and supraspinal mechanisms, which are important components of acute and chronic pain. This narrative review highlights the most relevant mechanisms of pain relief by spinal manipulation and provides a perspective for future research on spinal manipulation and spine pain, including the validation of placebo interventions that control for placebo effects and other non-specific effects that may be induced by spinal manipulation

Beneficial effects of manually assisted chiropractic adjusting instrument in a rabbit model of osteoarthritis.

Osteoarthritis (OA) is a degenerative disease characterized by injury of all joint tissues. Our previous study showed that in experimental osteoporosis, chiropractic manipulation (CM) exerts protective effects on bone. We here assessed whether CM might ameliorate OA by improving subchondral bone sclerosis, cartilage integrity and synovitis. Male New-Zealand rabbits underwent knee surgery to induce OA by anterior cruciate ligament injury. CM was performed using the chiropractic instrument ActivatorV 3 times/week for 8 weeks as follows: force 2 setting was applied to the tibial tubercle of the rabbit right hind limb (TM-OA), whereas the corresponding left hind limb received a false manipulation (FM-OA) consisting of ActivatorV firing in the air and slightly touching the tibial tubercle. After sacrifice, subchondral bone integrity was assessed in the tibiae by microCT and histology. Cartilage damage and synovitis were estimated by Mankin's and Krenn's scores, respectively, and histological techniques. Bone mineral density and content in both cortical and trabecular compartments of subchondral bone decreased in OA rabbits compared to controls, but partially reversed in the TM-OA group. Trabecular bone parameters in the latter group also showed a significant improvement compared to FM-OA group. Moreover RANKL, OPG, ALP and TRAP protein expression in subchondral bone significantly decreased in TM-OA rabbits with respect to FM-OA group. CM was associated with lower Mankin's and Krenn's scores and macrophage infiltrate together with a decreased protein expression of pro-inflammatory, fibrotic and angiogenic factors, in TM-OA rabbits with respect to FM-OA. Our results suggest that CM may mitigate OA progression by improving subchondral bone as well as cartilage and synovial membrane status.AODM was supported by grants from the Spanish Chiropractic Association (AEQ). AM was supported by grants from Spanish Ministry of Economy and Competitiveness and Carlos III Institute of Health (CP15/00053 and PI16/00991). We thank Dr. Carlos Guillén-Viejo (School of Pharmacy, Universidad Complutense de Madrid) for his help in advising in molecular biology methods. The authors are also grateful to Mark S. Davis for his assistance with editing and proofreading the article.S

Parathyroid Hormone-Related Protein Promotes Inflammation in the kidney with an Obstructed ureter

Parathyroid hormone-related protein (PTHrP) promotes fibrogenesis in the acutely damaged kidney. Considering the relation between fibrosis and inflammation, we studied transgenic mice that overexpress PTHrP in the proximal tubule. When unilateral ureteric obstruction was induced in these transgenic mice, we found that they had more renal tubulointerstitial damage, leukocyte influx, and expression of proinflammatory factors than their control littermates. Reversal of PTHrP constitutive overexpression in these transgenic mice or treatment of control mice with the PTHrP antagonist (7–34) decreased this inflammatory response. Losartan, which abolished obstruction-induced endogenous PTHrP upregulation, also decreased the latter response but less effectively in transgenic mice. The PTHrP fragment (1–36) induced nuclear factor-jB (NF-jB) activation and proinflammatory cytokine overexpression in mouse cortical tubule cells in culture as well as migration of the macrophage cell line Raw 264.7. All these effects were decreased by PTHrP (7–34) and NF-jB or extracellular signal-regulated kinase (ERK) activation inhibitors. Our findings suggest a critical role of PTHrP in the renal inflammatory process that results from ureteral obstruction and indicate that ERK-mediated NF-jB activation seems to be an important mechanism whereby PTHrP triggers renal inflammatio

Urinary TNF-α as a potential biomarker for chronic primary low back pain

IntroductionOver two thirds of individuals with low back pain (LBP) may experience recurrent or persistent symptoms in the long term. Yet, current data do not allow to predict who will develop chronic low back pain and who will recover from an acute episode. Elevated serum levels of the proinflammatory cytokine tumor necrosis factor-α (TNF-α) have been associated with poor recovery and persistent pain following an acute episode of LBP. Inflammatory cytokines may also mediate mechanisms involved in nociplastic pain, and thus, have significant implications in chronic primary low back pain (CPLBP).MethodsThis study aimed to investigate the potential of urinary TNF-α levels for predicting outcomes and characterizing clinical features of CPLBP patients. Twenty-four patients with CPLBP and 24 sex- and age-matched asymptomatic controls were recruited. Urinary TNF-α concentrations were measured at baseline and after 4 weeks, during which CPLBP patients underwent spinal manipulative therapy (SMT).ResultsConcentrations of TNF-α were found to be elevated in baseline urine samples of CPLBP patients compared to asymptomatic controls. Moreover, these values differed among patients depending on their pain trajectory. Patients with persistent pain showed higher levels of TNF-α, when compared to those with episodic CPLBP. Furthermore, baseline TNF-α concentrations and their changes after 4 weeks predicted alterations in pain intensity and disability following SMT in patients with CPLBP.DiscussionThese findings warrant further research on the potential use of urinary TNF-α concentrations as a prognostic biomarker for CPLBP

Interacción entre la angiotensina II y la proteína relacionada con la parathormona: estudio en un modelo de fracaso renal agudo por ácido fólico

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid. Facultad de Medicina, Departamento de Bioquímica. Fecha de lectura: 22 de Abril 200

Characterisation of the correlation between standing lordosis and degenerative joint disease in the lower lumbar spine in women and men: a radiographic study

Abstract Background Degenerative joint disease (DJD) in the lumbar spine is a common condition that is associated with chronic low back pain. Excessive loading of lumbar joints is a risk factor for DJD. Changes in lumbar lordosis significantly redistribute the forces of weight-bearing on the facet joints and the intervertebral discs. However, the relationship between lumbar lordosis and DJD has not been characterized in men and women. Methods We characterised the correlation between standing lumbar lordosis and DJD in standing radiographic images from 301 adult female and male chiropractic patients. DJD was rated using the Kellgren-Lawrence scale, and lordosis was measured using the Cobb angle. Linear and curvilinear correlations were investigated while controlling for age and sex. Results We found a highly significant curvilinear correlation between lordosis and DJD of the lower lumbar spine in both sexes, but especially in women, irrespective of the effects of age. We found the effect size of lordosis on lower lumbar DJD to be between 17.4 and 18.1% in women and 12.9% in older men. In addition, lordosis of 65 (95% CI 55.3–77.7) and 68 (98% CI 58.7–73.3) degrees were associated with minimal DJD in the lower lumbar spine of women and men respectively, and were therefore considered ‘optimal’. This optimal lordotic angle was 73 (95% CI 58.8–87.2) degrees in older men. Conclusions Both hypo- and hyper-lordosis correlate with DJD in the lumbar spine, particularly in women and in older men. These findings may well be of relevance to spinal pain management and spinal rehabilitation

From hands-on to remote:Moderators of response to a novel self-management telehealth programme during the COVID-19 pandemic

BACKGROUND: In March 2020, state‐wide lockdowns were declared in many countries, including Spain. Citizens were confined to their homes and remotely supported activities were prioritized as an alternative to in‐person interactions. Previous data suggest that remote and self‐management interventions may be successful at reducing pain and related psychological variables. However, individual factors influencing the effectiveness of these interventions remain to be identified. We aimed to investigate the psychological and motivational factors moderating changes in pain observed in chiropractic patients undertaking a novel telehealth self‐management programme. METHODS: A cohort of 208 patients from a chiropractic teaching clinic was recruited to participate in the study. Patients received telehealth consultations and individualized self‐management strategies tailored for their current complaint. They were encouraged to make use of these strategies daily for 2–4 weeks, whilst rating their pain intensity, motivation and adherence. Validated questionnaires were completed online to assess catastrophizing, kinesiophobia and anxiety. RESULTS: A total of 168 patients completed the first 2 weeks of the programme, experiencing significant reductions in all variables. Kinesiophobia emerged as a key factor influencing pain reduction and moderating the association between motivation and pain relief. In turn, adherence to the programme was associated with lower pain intensity, although moderated by the degree of motivation. CONCLUSIONS: In the context of COVID‐19, when introducing remote and self‐management strategies, pain cognitions and motivational factors should be taken into consideration to foster adherence and yield better pain outcomes