Pain
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Diabetic peripheral neuropathy (DPN) affects up to 50% of patients with diabetes and is a major cause of morbidity and increased mortality. Its clinical manifestations include distressing painful neuropathic symptoms and insensitivity to trauma that result in foot ulcerations and amputations. Several recent studies have implicated poor glycemic control, duration of diabetes, hyperlipidemia (particularly hypertryglyceridaemia), elevated albumin excretion rates, and obesity as risk factors for the development of DPN. ⋯ Moreover, although there is now strong evidence for the importance of peripheral nerve microvascular disease in the pathogenesis of DPN, peripheral structural biomarkers of painful DPN are lacking. However, there is now emerging evidence for the involvement of the central nervous system in both painful and painless DPN afforded by magnetic resonance imaging. This review will focus on this emerging evidence for central changes in DPN, hitherto considered a peripheral nerve disease only.
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The information from nociceptors is processed in the dorsal horn of the spinal cord by complex circuits involving excitatory and inhibitory interneurons. It is well documented that GluN2B and ERK1/2 phosphorylation contributes to central sensitization. Striatal-enriched protein tyrosine phosphatase (STEP) dephosphorylates GluN2B and ERK1/2, promoting internalization of GluN2B and inactivation of ERK1/2. ⋯ Consistently, STEP knockout mice failed to show age-related thermal hyperalgesia, although gender-related differences were preserved. Moreover, in a model of inflammatory pain, hyperalgesia was associated with increased phosphorylation-mediated STEP(61) inactivation and increased pGluN2B(Tyr1472) and pERK1/2(Thr202/Tyr204)levels in the lumbar spinal cord. Collectively, the present results underscore an important role of spinal STEP activity in the modulation of nociception.
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Substantial evidence has implicated microglia in neuropathic pain. After peripheral nerve injury, microglia in the spinal cord proliferate and increase cell-surface expression of the purinergic receptor P2X4. Activation of P2X4 receptors results in release of brain-derived neurotrophic factor, which acts on neurons to produce disinhibition of dorsal horn neurons which transmit nociceptive information to the brain. ⋯ Despite similar microglia proliferation in the dorsal horn in both sexes, females do not upregulate P2X4Rs and use a microglia-independent pathway to mediate pain hypersensitivity. Instead, adaptive immune cells, possibly T cells, may mediate pain hypersensitivity in female mice. This profound sex difference highlights the importance of including subjects of both sexes in preclinical pain research.