Accepted

Degenerative disc disease of the lumbosacral spine is a very common medical problem. An episode of sciatica occurs at least once in the life of 60-90% of the human population. A phenomenon that is closely related to the process of lowering the pH of the extracellular matrix degenerating the intervertebral disc (IVD) is the precipitation of calcium salts, especially pyrophosphate dehydrate and hydroxyapatite. In such an altered environment of the IVD, we can observe an increased influx of monocytes, macrophages, T-lymphocytes, as well as non-immunocompetent cells, which are a source of cytokines, e.g., tumor necrosis alpha (TNF-α), Interleukin- (IL-1β, IL-8). The above-mentioned mediators of an inflammatory condition contribute to an increase in the expression of Brain-Derived Neurotrophic Factor (BDNF) and Glial cell Derived Neurotrophic Factor (GDNF) in mast cells and chondrocytes, as well as to the descending transport of these mediators along the nerve endings. In the process of degeneration of the IVD as a result of repeated and even slight injuries, there is damage to the connections of the endplate of the vertebral bodies with the IVD, which results in an impairment of the penetration of nutritional substances and water into the disc. As a consequence, there is an overexpression of the brain-derived neurotrophic factor GDNF, as well as neuromodulin (GAP-43) in the mast cells, chondrocytes of the IVDs, while descending transport of these mediators along the nerve fibers is also observed.

A growing body of evidence has shown that people with chronic low back pain (CLBP) demonstrate significantly greater declines in multiple cognitive domains than people who do not have CLBP. Given the high prevalence of CLBP in the ever-growing aging population that may be more vulnerable to cognitive decline, it is important to understand the mechanisms underlying the accelerated cognitive decline observed in this population, so that proper preventive or treatment approaches can be developed and implemented. The current scoping review summarizes what is known regarding the potential mechanisms underlying suboptimal cognitive performance and cognitive decline in people with CLBP and discusses future research directions. Five potential mechanisms were identified based on the findings from 34 included studies: (1) altered activity in the cortex and neural networks; (2) grey matter atrophy; (3) microglial activation and neuroinflammation; (4) comorbidities associated with CLBP; and (5) gut microbiota dysbiosis. Future studies should deepen the understanding of mechanisms underlying this association so that proper prevention and treatment strategies can be developed.

Nerve injury-induced neuropathic pain is a type of chronic pain associated with neuroinflammatory response and neuronal death; however the underlying molecular mechanisms are still unclear. Dual-specificity phosphatase 8 (DUSP8) can mediate numerous cellular events, but whether it's involved in neuropathic pain is unknown. In the study, we found that spinal nerve ligation (SNL) operation on rats significantly decreased DUSP8 expression levels in ipsilateral spinal cord (ISC) tissues. Consistently, lipopolysaccharide (LPS) exposure also reduced DUSP8 in murine microglial cells. Adeno-associated virus (AAV)-mediated DUSP8 over-expression was found to considerably ameliorate SNL-induced neuropathic pain in rats. Additionally, neuronal death in the ISC tissues was also attenuated by AAV-DUSP8 following SNL surgery. Moreover, SNL-triggered neuroinflammation and microglial activation were also mitigated upon DUSP8 over-expression by suppressing nuclear factor κB (NF-κB) signaling, which were validated in LPS-exposed microglial cells. Importantly, our in vitro experiments indicated that inflammatory response in microglial cells contributed to neuron death, and such effect could also be ameliorated by DUSP8 over-expression. Notably, we found that DUSP8 directly interacted with transforming growth factor β activated kinase-1 (TAK1) in microglial cells. Both SNL and LPS led to the activation of TAK1/p38/JNK1/2 signaling, whereas being strongly abolished by DUSP8. Intriguingly, TAK1 blockage significantly diminished LPS-induced inflammation and neuron death, whereas being accelerated by DUSP8 knockdown, further indicating that DUSP8-ameliorated neuropathic pain was largely TAK1-dependent. Together, all our findings revealed that DUSP8/TAK1 signaling may be a potential target for neuropathic pain alleviation.

Pain intensity is well-known to be influenced by a wide range of biobehavioral variables. Nutritional factors, however, have not been generally considered for their potential importance. This cross-sectional study examined associations between erythrocyte omega-6 (n-6) and omega-3 (n-3) polyunsaturated fatty acids (PUFAs) and pain intensity in 605 adults. Pain intensity was computed on a 0-100 numeric rating scale from questions about five chronic pain conditions: orofacial pain, headache, low back pain, irritable bowel syndrome, and bodily pain. For each pain condition, multiple linear regression tested the hypothesis that a higher ratio of n-6 arachidonic acid to the sum of n-3 eicosapentaenoic acid and docosahexaenoic acid (AA/(EPA+DHA) was associated with greater pain intensity. In covariate-adjusted analysis, orofacial pain intensity increased 5.7 points (95% CI: 1.4, 9.9) per unit increase in n-6/n-3 PUFA ratio. Likewise, a one unit increase in n-6/n-3 PUFA ratio was associated with significant increases in pain intensity (range 5-8 points) of headache pain, low back pain, and bodily pain, but not abdominal pain. Separate multiple linear regression models investigated the independent strength of association of individual PUFAs to the intensity of each pain condition. Overall, n-3 docosahexaenoic acid was most strongly, and inversely, associated with pain intensity. PERSPECTIVE: Perspective: A higher ratio of n-6/n-3 long-chain polyunsaturated fatty acids was associated greater pain intensity for orofacial pain, headache, low back pain, and bodily pain, but not abdominal pain. The n-6/n-3 PUFA ratio was more consistently associated with pain intensity than any individual constituent of the long-chain PUFA ratio.

Phantom limb pain (PLP) is a common type of chronic pain that occurs after limb amputation. Many treatment approaches are available, however, the treatment of PLP is still a challenge. This study aimed to quantify and rank the efficacy of interventions for phantom limb pain.