Browse by Audience
Nociceptive pain is a hallmark of many chronic inflammatory conditions including inflammatory bowel diseases (IBDs); however, whether pain-sensing neurons influence intestinal inflammation remains poorly defined. Employing chemogenetic silencing, adenoviral-mediated colon-specific silencing, and pharmacological ablation of TRPV1 nociceptors, we observed more severe inflammation and defective tissue-protective reparative processes in a murine model of intestinal damage and inflammation. Disrupted nociception led to significant alterations in the intestinal microbiota and a transmissible dysbiosis, while mono-colonization of germ-free mice with GramClostridium spp. promoted intestinal tissue protection through a nociceptor-dependent pathway. Mechanistically, disruption of nociception resulted in decreased levels of substance P, and therapeutic delivery of substance P promoted tissue-protective effects exerted by TRPV1 nociceptors in a microbiota-dependent manner. Finally, dysregulated nociceptor gene expression was observed in intestinal biopsies from IBD patients. Collectively, these findings indicate an evolutionarily conserved functional link between nociception, the intestinal microbiota, and the restoration of intestinal homeostasis.
Learn More >Multiple clinical trials with different exercise protocols have demonstrated efficacy in the management of migraine. However, there is no head-to-head comparison of efficacy between the different exercise interventions.
Learn More >Active duty (AD) women suffer with chronic pelvic pain (CPP) while providers tackle diagnoses and treatments to keep them functional without contributing to the opioid epidemic. The purpose of this randomized trial was to determine the effectiveness of noninvasive, self-explanatory mindfulness-based stress reduction (MBSR) or self-paced healthy lifestyle (HL) interventions on CPP in AD women. A 6-week, interventional prospective study with AD women aged 21-55 years at Mountain Home (MTHM), Idaho, was conducted. Women were randomly assigned to MBSR ( = 21) or HL ( = 20) interventions. The primary outcome was pain perception. The secondary outcomes were depression and circulating cytokine levels. Women in the MBSR group exhibited reduced pain interference ( < 0.01) and depression ( < 0.05) alongside decreased interleukin (IL)-4 ( < 0.05), IL-6 ( < 0.05), eotaxin ( < 0.05), monocyte chemoattractant protein-1 ( = 0.06), and interleukin-1 receptor antagonist (IL-1ra) ( < 0.01) and increased vascular endothelial growth factor ( < 0.05). Women in the HL group did not have changes in pain; however, they did exhibit reduced depression ( < 0.05) alongside decreased granulocyte-macrophage colony-stimulating factor ( < 0.05) and increased tumor necrosis factor alpha ( < 0.05), stromal cell-derived factor-1 ( < 0.01), and IL-1ra ( < 0.01). AD women receiving MBSR or HL had reduced depression scores and altered circulating cytokine levels; however, only those receiving MBSR had reduced pain perception. Findings support MBSR as an effective and viable behavioral treatment for AD women suffering from CPP and provide premise for larger randomized controlled studies. MOCHI-An RCT of mindfulness as a treatment for CPP in AD Women NCT04104542 (September 26, 2019).
Learn More >Inflammation plays an important role in the development of rheumatoid arthritis (RA). NR4A1 is an anti-inflammatory orphan nuclear receptor involved in protection from inflammatory stimuli in RA. In this study we have explored the anti-inflammatory potential of the FDA-approved drug 9-aminoacridine (9AA) and the natural compound caffeic acid (CA) conjugated to nanomicelles for the treatment of RA. We have synthesized methoxy polyethylene glycol polycaprolactone block copolymer (mPEG–PCL) by ring opening polymerization of ε-caprolactone. Then, we conjugated the hydrophilic caffeic acid (CA) with mPEG–PCL micelles via Steglich esterification and incorporated the 9AA drug. These nanomicelles were formulated by the solvent evaporation method with a size distribution around 190 nm and showed maximum drug loading capacity along with sustained drug release behavior. Furthermore, we tested the therapeutic potential of the formulated 9AA-encapsulated CA-conjugated nanomicelles (9AA-NMs) against an experimental RA model. We observed promising results which showed alleviation of arthritic symptoms by reducing inflammation, joint damage, bone erosion, and swelling. Further, collagen destruction was significantly reduced in articular cartilage, as shown by safranin-O and toluidine blue staining. The protective mechanism might be due to the simultaneous inhibition of NF-κB by 9AA and CA, whereas the activation of NR4A1 by 9AA leads to the suppression of HIF-1α. This combined therapeutic effect of 9AA and CA has enhanced the therapeutic efficacy of 9AA-NM and markedly reduced the severity of inflammatory arthritis. Unlike existing drugs for pain management and with limited efficacy, 9AA-NM exerted a disease-relevant activation/blockade that alleviated inflammation and exhibited marked therapeutic efficacy against RA.
Learn More >Repetitive opioid use does not always alleviate basal pain, procedural pain, or both after burn injury. Mitigation of burn injury-site pain can be achieved by GTS-21 stimulation of α7-acetylcholine nicotinic receptors (α7AChRs) and reduced microglia activation in rat. We tested the hypothesis that morphine exaggerates burn injury-site pain and GTS-21 alleviates both morphine-induced aggravated burn injury pain and microglia activation.
Learn More >Sensory innervation of the skin is essential for its function, homeostasis and wound healing mechanisms. Thus, to adequately model the cellular microenvironment and function of native skin, in vitro human skin equivalents (hSE) containing a sensory neuron population began to be researched. In this work, we established a fully human three-dimensional (3D) platform of hSE innervated by induced pluripotent stem cell-derived nociceptors neurospheres (hNNs), mimicking the native mode of innervation. Both the hSE and nociceptor population exhibited morphological and phenotypical characteristics resembling their native counterparts, such as epidermal and dermal layer formation and nociceptor marker exhibition, respectively. In the co-culture platform, neurites developed from the hNNs and navigated in 3D to innervate the hSE from a distance. To probe both skin and nociceptor functionality, we applied a clinically available capsaicin patch (Qutenza™) directly over the hSE section and analyzed neuron reaction. Application of the patch caused an exposure time-dependent neurite regression and degeneration. In platforms absent of hSE, axonal degeneration was further increased, highlighting the role of the skin construct as a barrier. In sum, we established an in vitro tool of functional innervated skin with high interest for preclinical research. This article is protected by copyright. All rights reserved.
Learn More >Osteoarthritis (OA) is a degenerative joint disease and is the main cause of chronic pain and functional disability in adults. Articular cartilage is a hydrated soft tissue that is composed of normally quiescent chondrocytes at a low density, a dense network of collagen fibrils with a pore size of 60-200 nm, and aggrecan proteoglycans with high-density negative charge. Although certain drugs, nucleic acids, and proteins have the potential to slow the progression of OA and restore the joints, these treatments have not been clinically applied owing to the lack of an effective delivery system capable of breaking through the cartilage barrier. Recently, the development of nanotechnology for delivery systems renders new ideas and treatment methods viable in overcoming the limited penetration. In this review, we focus on current research on such applications of nanotechnology, including exosomes, protein-based cationic nanocarriers, cationic liposomes/solid lipid nanoparticles, amino acid-based nanocarriers, polyamide derivatives-based nanocarriers, manganese dioxide, and carbon nanotubes. Exosomes are the smallest known nanoscale extracellular vesicles, and they can quickly deliver nucleic acids or proteins to the required depth. Through electrostatic interactions, nanocarriers with appropriate balance in cationic property and particle size have a strong ability to penetrate cartilage. Although substantial preclinical evidence has been obtained, further optimization is necessary for clinical transformation. STATEMENT OF SIGNIFICANCE: : The dense cartilage matrix with high-negative charge was associated with reduced therapeutic effect in osteoarthritis patients with deep pathological changes. However, a systematic review in nanodevices for deep cartilage penetration is still lacking. Current approaches to assure penetration of nanosystems into the depth of cartilage were reviewed, including nanoscale extracellular vesicles from different cell lines and nanocarriers with appropriate balance in cationic property and size particle. Moreover, nanodevices entering clinical trials and further optimization were also discussed, providing important guiding significance to future research.
Learn More >This study assessed the impact of cancer-related neuropathic pain (CRNP) on patients and the importance of the patient-healthcare professional (HCP) relationship in diagnosis and management.
Learn More >Benzodiazepines (BZDs), a class of sedative-hypnotic medications, generated concern as their popularity grew, with particular alarm regarding elevated rates of BZD use among chronic pain populations. Consistent with negative reinforcement/motivational models of substance use, desire for pain alleviation may motivate BZD use. Yet, little is known about relations between pain and addiction-relevant BZD use processes. This cross-sectional survey study aimed to: a) test associations between pain intensity and clinically relevant BZD use patterns, and b) examine the role of pain catastrophizing in hypothesized pain-BZD relations. Participants included 306 adults with chronic musculoskeletal pain and a current BZD prescription who completed an online survey study (M = 38.7, 38.9% female). Results indicated that pain intensity was positively associated with past-month BZD use frequency, BZD dependence severity, and likelihood of endorsing BZD misuse behaviors (ps < .05). Pain catastrophizing was positively associated with BZD dependence/likelihood of BZD misuse, covarying for pain intensity (p < .05). These findings build upon an emerging literature by highlighting positive covariation of pain intensity and pain catastrophizing with addiction-relevant BZD use behaviors. Results underscore the need to further investigate high-risk BZD use among individuals with chronic pain, with and without concurrent opioid use, to inform prevention/intervention efforts. PERSPECTIVE: : This article presents findings on cross-sectional associations of pain intensity and pain catastrophizing with clinically relevant benzodiazepine (BZD) use outcomes, including dependence and misuse, among individuals with chronic pain. Findings help elucidate the higher burden of BZD misuse/dependence in chronic pain populations and suggest that pain relief may be a common, yet underrecognized, self-reported motivation for taking BZDs.
Learn More >