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Degenerative IVD conditioned media and acidic pH sensitize sensory neurons to cyclic tensile strain.

ABSTRACT: Low back pain is among the leading causes of disability worldwide. The degenerative intervertebral disc (IVD) environment contains pathologically high levels of inflammatory cytokines and acidic pH hypothesized to contribute to back pain by sensitizing nociceptive neurons to stimuli that would not be painful in healthy patients. We hypothesized that the degenerative IVD environment drives discogenic pain by sensitizing nociceptive neurons to mechanical loading. To test this hypothesis, we developed an in vitro model that facilitated the investigation of interactions between the degenerative IVD environment, nociceptive neurons innervating the IVD and mechanical loading of the disc; and, the identification of the underlying mechanism of degenerative IVD induced nociceptive neuron sensitization. In our model, rat dorsal root ganglia (DRG) neurons were seeding onto bovine annulus fibrosus tissue, exposed to degenerative IVD conditioned media and/or acidic pH, and subjected to cyclic tensile strain (1 Hz; 1%-6% strain) during measurement of DRG sensory neuron activity via calcium imaging. Using this model, we demonstrated that both degenerative IVD conditioned media and degenerative IVD acidic pH levels induced elevated nociceptive neuron activation in response to physiologic levels of mechanical strain. In addition, interleukin 6 (IL-6) was demonstrated to mediate degenerative IVD conditioned media induced elevated nociceptive neuron activation. These results demonstrate IL-6 mediates degenerative IVD induced neuron sensitization to mechanical loading and further establishes IL-6 as a potential therapeutic target for the treatment of discogenic pain. Data further suggests the degenerative IVD environment contains multiple neuron sensitization pathways (IL-6, pH) that may contribute to discogenic pain.

SUBMITTER: Stover JD

PROVIDER: S-EPMC9265139 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Abstract Background Low back pain is a major contributor to disability worldwide and generates a tremendous socioeconomic impact. The degenerative intervertebral disc (IVD) has been hypothesized to contribute to discogenic pain by sensitizing nociceptive neurons innervating the disc to stimuli that is nonpainful in healthy patients. Previously, we demonstrated the ability of degenerative IVDs to sensitize neurons to mechanical stimuli; however, elucidation of degenerative IVDs discogenic pain mechanisms is required to develop therapeutic strategies that directly target these mechanisms. Aims In this study, we utilized CRISPR epigenome editing of nociceptive neurons to identify mechanisms of degenerative IVD‐induced changes to mechanical nociception and demonstrated the ability of multiplex CRISPR epigenome editing of nociceptive neurons to modulate inflammation‐induced mechanical nociception. Methods and Results Utilizing an in vitro model, we demonstrated degenerative IVD‐produced IL‐6‐induced increases in nociceptive neuron activity in response to mechanical stimuli, mediated by TRPA1, ASIC3, and Piezo2 ion channel activity. Once these ion channels were identified as mediators of degenerative IVD‐induced mechanical nociception, we developed singleplex and multiplex CRISPR epigenome editing vectors that modulate endogenous expression of TRPA1, ASIC3, and Piezo2 via targeted gene promoter histone methylation. When delivered to nociceptive neurons, the multiplex CRISPR epigenome editing vectors abolished degenerative IVD‐induced mechanical nociception while preserving nonpathologic neuron activity. Conclusion This work demonstrates the potential of multiplex CRISPR epigenome editing as a highly targeted gene‐based neuromodulation strategy for the treatment of discogenic pain, specifically; and, for the treatment of inflammatory chronic pain conditions, more broadly. Multiplex CRISPR epigenome editing of ion channel expression in nociceptive neurons abolished degenerative IVD‐induced mechanical nociception in an in vitro model of discogenic back pain. These results demonstrate multiplex epigenome editing of nociceptive neurons as a potential neuromodulation strategy for discogenic back pain and other chronic pain conditions.

Project description:Food contamination due to metal corrosion and the consequent leakage of metals into foods is a problem. Understanding the mechanism(s) of metal corrosion in food media is vital to evaluating, mitigating, and predicting contamination levels. Fruit juices have been employed as model corrosive media to study the corrosion behaviour of metallic material in food media. Carbon steel corrosion in fresh juices of tomato, orange, pineapple, and lemon, as well as dilute hydrochloric acid solutions at varied pH, was studied using scanning electron microscopy, gravimetric and spectrophotometric techniques, and comparisons made between the corrosivity of these juices and mineral acids of comparable pH. The corrosion of carbon steel in fruit juices and HCl solutions manifests as a combination of uniform and pitting corrosion. Gravimetric data acquired after one hour of immersion at ambient temperature (22 °C) indicated corrosion rates of 0.86 mm yr-1 in tomato juice (pH ≈ 4.24), 1.81 mm yr-1 in pineapple juice (pH ≈ 3.94), 1.52 mm yr-1 in orange juice (pH ≈ 3.58), and 2.89 mm yr-1 in lemon juice (pH ≈ 2.22), compared to 2.19 mm yr-1 in 10-2 M HCl (pH ≈ 2.04), 0.38 mm yr-1 in 10-3 M HCl (pH ≈ 2.95), 0.17 mm yr-1 in 10-4 M HCl (pH ≈ 3.95), and 0.04 mm yr-1 in 10-5 M HCl (pH ≈ 4.98). The correlation of gravimetrically acquired corrosion data with post-exposure spectrophotometric analysis of fruit juices enabled de-convolution of iron contamination rates from carbon steel corrosion rates in fruit juices. Elemental iron contamination after 50 h of exposure to steel samples was much less than the values predicted from corrosion data (≈40%, 4.02%, 8.37%, and 9.55% for tomato, pineapple, orange, and lemon juices, respectively, relative to expected values from corrosion (weight loss) data). Tomato juice (pH ≈ 4.24) was the least corrosive to carbon steel compared to orange juice (pH ≈ 3.58) and pineapple juice (pH ≈ 3.94). The results confirm that though the fruit juices are acidic, they are generally much less corrosive to carbon steel compared to hydrochloric acid solutions of comparable pH. Differences in the corrosion behaviour of carbon steel in the juices and in the different mineral acid solutions are attributed to differences in the compositions and pH of the test media, the nature of the corrosion products formed, and their dissolution kinetics in the respective media. The observation of corrosion products (iron oxide/hydroxide) in some of the fruit juices (tomato, pineapple, and lemon juices) in the form of apparently hollow microspheres indicates the feasibility of using fruit juices and related wastes as "green solutions" for the room-temperature and hydrothermal synthesis of metal oxide/hydroxide particles.

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Degenerative IVD conditioned media and acidic pH sensitize sensory neurons to cyclic tensile strain.

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