Accepted

This review describes the roles of the low-density lipoprotein receptor-related protein 1 (LRP-1) in inflammatory pathways, nerve nerve degeneration and -regeneration and in neuropathic pain. Induction of LRP-1 is able to reduce the activation of the proinflammatory NFκB-mediated pathway and the mitogen-activated protein kinase (MAPK) c-Jun N-terminal kinase and p38 signaling pathways, in turn decreasing the production of inflammatory mediators. Low-density lipoprotein receptor-related protein 1 activation also decreases reactive astrogliosis and polarizes microglial cells and macrophages from a proinflammatory phenotype (M1) to an anti-inflammatory phenotype (M2), attenuating the neuroinflammatory environment. Low-density lipoprotein receptor-related protein 1 can also modulate the permeability of the blood-brain barrier and the blood-nerve barrier, thus regulating the infiltration of systemic insults and cells into the central and the peripheral nervous system, respectively. Furthermore, LRP-1 is involved in the maturation of oligodendrocytes and in the activation, migration, and repair phenotype of Schwann cells, therefore suggesting a major role in restoring the myelin sheaths upon injury. Low-density lipoprotein receptor-related protein 1 activation can indirectly decrease neurodegeneration and neuropathic pain by attenuation of the inflammatory environment. Moreover, LRP-1 agonists can directly promote neural cell survival and neurite sprouting, decrease cell death, and attenuate pain and neurological disorders by the inhibition of MAPK c-Jun N-terminal kinase and p38-pathway and activation of MAPK extracellular signal-regulated kinase pathway. In addition, activation of LRP-1 resulted in better outcomes for neuropathies such as Alzheimer disease, nerve injury, or diabetic peripheral neuropathy, attenuating neuropathic pain and improving cognitive functions. To summarize, LRP-1 plays an important role in the development of different experimental diseases of the nervous system, and it is emerging as a very interesting therapeutic target.

A plethora of evidence supports the existence of neuromuscular changes in people with chronic spinal pain (neck and low back pain), yet it is unclear whether neuromuscular adaptations persist for people with recurrent spinal pain when in a period of remission. This systematic review aimed to synthesise the evidence on neuromuscular adaptations in people with recurrent spinal pain during a period of remission. Electronic databases, grey literature, and key journals were searched from inception up to the 4th of September 2020. Eligibility criteria included observational studies investigating muscle activity, spine kinematics, muscle properties, sensorimotor control, and neuromuscular performance in adults (≥ 18 years) with recurrent spinal pain during a period of remission. Screening, data extraction, and quality assessment (Newcastle-Ottawa Scale) were conducted independently by two reviewers. Data synthesis was conducted per outcome domain. A meta-analysis with a random-effects model was performed where possible. The overall strength of evidence was rated using the Grading of Recommendations, Assessment, Development and Evaluation guidelines (GRADE). From 8292 records, 27 and five studies were included in a qualitative and quantitative synthesis, respectively. Very low level of evidence supports muscle activity changes in people with recurrent low back pain, especially greater co-contraction, redistribution of muscle activity, and delayed postural control of deeper trunk muscles. Reduced range of motion of the lumbar spine was also found. Meaningful conclusions regarding other outcome domains or people with recurrent neck pain could not be drawn. In conclusion, people with recurrent low back pain during a period of remission show muscle activity and spine kinematics adaptations. Future research should investigate the long-term impact of these changes, as well as adaptations in people with recurrent neck pain.

Pain is a major and common symptom reported as a top priority in patients with rheumatoid arthritis (RA). Intuitively, RA-related pain is often considered to be a natural consequence of peripheral inflammation, so treatment of RA is expected to manage pain concurrently as part of inflammation control. However, pain in patients with RA can be poorly correlated with objective measures of inflammation, for example, in patients who are otherwise in remission. Joint damage appears to account for only a fraction of this residual pain. Emerging evidence suggests that alteration of peripheral and central pain processing contributes to RA-related pain; this is parallel to, but somewhat independent of, joint inflammation. Interleukin (IL)-6 is a proinflammatory cytokine that contributes to the pathogenesis of RA. It exerts systemic effects via signaling through soluble forms of the IL-6 receptor ("trans-signaling"). Evidence from preclinical studies demonstrates that intra-articular IL-6 can produce long-lasting peripheral sensitization to mechanical stimulation and suggests an important role for IL-6 in central pain sensitization. This may be partly explained by its ability to activate neurons through trans-signaling, affecting nociceptive plasticity and nerve fiber regrowth. Local activity at neuron endings may culminate in altered pain processing in the central nervous system because of persistent signaling from sensitized peripheral neurons. Peripheral and central sensitization can promote the development of chronic pain, which can have a significant impact on patients' health and quality of life. A proportion of pain in RA may be more appropriately managed as an entity separate from inflammation. Both the peripheral and central nervous systems should be recognized as important potential systems targeted by RA. The substantial burden of RA-related chronic pain suggests that pain should be a key focus in RA management and should be assessed and addressed early and separately from the inflammatory component.