Highly efficient antioxidants based on superoxide dismutase (SOD) -loaded porous polymersomes are developed for treating neuropathic pain. The SOD-loaded porous polymersomes are highly permeable to superoxide radical, while retaining the antioxidant enzyme within their aqueous interiors. Administration of the antioxidant porous polymersomes following a painful nerve root compression is substantially more effective in preventing the onset of pain in rats than comparable or higher doses of free SOD alone.
Chronic joint pain is a widespread problem that frequently occurs with aging and trauma. Pain occurs most often in synovial joints, the body's load bearing joints. The mechanical and molecular mechanisms contributing to synovial joint pain are reviewed using two examples, the cervical spinal facet joints and the temporomandibular joint (TMJ). Although much work has focused on the macroscale mechanics of joints in health and disease, the combined influence of tissue mechanics, molecular processes, and nociception in joint pain has only recently become a focus. Trauma and repeated loading can induce structural and biochemical changes in joints, altering their microenvironment and modifying the biomechanics of their constitutive tissues, which themselves are innervated. Peripheral pain sensors can become activated in response to changes in the joint microenvironment and relay pain signals to the spinal cord and brain where pain is processed and perceived. In some cases, pain circuitry is permanently changed, which may be a potential mechanism for sustained joint pain. However, it is most likely that alterations in both the joint microenvironment and the central nervous system (CNS) contribute to chronic pain. As such, the challenge of treating joint pain and degeneration is temporally and spatially complicated. This review summarizes anatomy, physiology, and pathophysiology of these joints and the sensory pain relays. Pain pathways are postulated to be sensitized by many factors, including degeneration and biochemical priming, with effects on thresholds for mechanical injury and/or dysfunction. Initiators of joint pain are discussed in the context of clinical challenges including the diagnosis and treatment of pain.
Degeneration is a hallmark of painful joint disease and is mediated by many proteases that degrade joint tissues, including collagenases. We hypothesized that purified bacterial collagenase would initiate nociceptive cascades in the joint by degrading the capsular ligament’s matrix and activating innervating pain fibers. Intra-articular collagenase in the rat facet joint was investigated for its effects on behavioral sensitivity, joint degeneration, and nociceptive pathways in the peripheral and central nervous systems. In parallel, a co-culture collagen gel model of the ligament was used to evaluate effects of collagenase on microscale changes to the collagen fibers and embedded neurons. Collagenase induced sensitivity within one day, lasting for 3 weeks (p < 0.001) but did not alter ligament structure, cartilage health, or chondrocyte homeostasis. Yet, nociceptive mediators were increased in the periphery (substance P, pERK, and MMP-1; p ≤ 0.039) and spinal cord (substance P and MMP-1; p ≤ 0.041). The collagen loss (p = 0.008) induced by exposing co-cultures to collagenase was accompanied by altered neuronal activity (p = 0.002) and elevated neuronal MMP-1 (p < 0.001), suggesting microscale collagen degradation mediates sensitivity in vivo. The induction of sustained sensitivity and nociception without joint damage may explain the clinical disconnect in which symptomatic joint pain patients present without radiographic evidence of joint destruction.
Treating persistent neuropathic pain remains a major clinical challenge. Current conventional treatment approaches carry a substantial risk of toxicity and provide only transient pain relief. In this work, we show that the activity and expression of the inflammatory mediator secretory phospholipase-A2 (sPLA2) enzyme increases in the spinal cord after painful nerve root compression. We then develop phospholipid micelle-based nanoparticles that release their payload in response to sPLA2 activity. Using a rodent model of neuropathic pain, phospholipid micelles loaded with the sPLA2 inhibitor, thioetheramide-PC (TEA-PC), are administered either locally or intravenously at the time of painful injury or 1–2 days afterward. Local micelle administration immediately after compression prevents pain for up to 7 days. Delayed intravenous administration of the micelles attenuates existing pain. These findings suggest that sPLA2 inhibitor-loaded micelles can be a promising anti-inflammatory nanotherapeutic for neuropathic pain treatment.
Abnormal loading of a joint's ligamentous capsule causes pain by activating the capsule's nociceptive afferent fibers, which reside in the capsule's collagenous matrix alongside fibroblast-like synoviocytes (FLS) and transmit pain to the dorsal root ganglia (DRG). This study integrated FLS into a DRG-collagen gel model to better mimic the anatomy and physiology of human joint capsules; using this new model, the effect of FLS on multiscale biomechanics and cell physiology under load was investigated. Primary FLS cells were co-cultured with DRGs at low or high concentrations, to simulate variable anatomical FLS densities, and failed in tension. Given their roles in collagen degradation and nociception, matrix-metalloproteinase (MMP-1) and neuronal expression of the neurotransmitter substance P were probed after gel failure. The amount of FLS did not alter (p > 0.3) the gel failure force, displacement, or stiffness. FLS doubled regional strains at both low (p < 0.01) and high (p = 0.01) concentrations. For high FLS, the collagen network showed more reorganization at failure (p < 0.01). Although total MMP-1 and neuronal substance P were the same regardless of FLS concentration before loading, protein expression of both increased after failure, but only in low FLS gels (p ≤ 0.02). The concentration-dependent effect of FLS on microstructure and cellular responses implies that capsule regions with different FLS densities experience variable microenvironments. This study presents a novel DRG-FLS co-culture collagen gel system that provides a platform for investigating the complex biomechanics and physiology of human joint capsules, and is the first relating DRG and FLS interactions between each other and their surrounding collagen network.
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