Pain
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Pain experience can change the central processing of nociceptive inputs, resulting in persistent allodynia and hyperalgesia. However, the underlying circuit mechanisms remain underexplored. Here, we focus on pain-induced remodeling of the projection from the mediodorsal thalamus (MD) to the anterior cingulate cortex (ACC), a projection that relays spinal nociceptive input for central processing. ⋯ After prolonged (∼30 days) CCI, injury-generated silent synapses declined to low levels, which likely resulted from a synaptic maturation process that strengthens AMPAR-mediated MD-to-ACC transmission. Consistent with this hypothesis, viral-mediated knockdown of GluN2B in ACC neurons, which prevented pain-induced generation of silent synapses and silent synapse-mediated strengthening of MD-to-ACC projection after prolonged CCI, prevented the development of allodynia. Taken together, our results depict a silent synapse-mediated mechanism through which key supraspinal neural circuits that regulate pain sensitivity are remodeled to induce allodynia and hyperalgesia.
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Chronic pain is highly prevalent in multiple sclerosis (MS). Pain heterogeneity may contribute to poor treatment outcomes. The aim of this study was to characterize pain phenotypes distributions in persons with MS and compare pain phenotypes in terms of pain intensity, frequency of chronic overlapping pain conditions, and use and analgesic effects of different classes of pain medications. ⋯ Although NSAID use was highest among those with nociplastic pain (80%), pain relief ratings for NSAIDs were highest among those with nociceptive pain. These findings underscore the need for multidimensional assessment of pain in MS with greater emphasis on the identification of pain phenotype. An improved characterization of pain as a multifaceted condition in MS could inform therapeutic approaches.
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Small-fiber neuropathy (SFN) has been traditionally considered as a pure disorder of the peripheral nervous system, characterized by neuropathic pain and degeneration of small-diameter nerve fibers in the skin. Previous functional magnetic resonance imaging studies revealed abnormal activations of pain networks, but the structural basis underlying such maladaptive functional alterations remains elusive. We applied diffusion tensor imaging to explore the influences of SFN on brain microstructures. ⋯ Furthermore, the degree of skin nerve degeneration, measured by intraepidermal nerve fiber density, was associated with the reduction of connectivity between the thalamus and pain-related areas according to different neuropathic pain phenotypes, specifically, the frontal, cingulate, motor, and limbic areas for burning, electrical shocks, tingling, mechanical allodynia, and numbness. Despite altered white matter connectivity, there was no change in white matter integrity assessed with fractional anisotropy. Our findings indicate that alterations in structural connectivity may serve as a biomarker of maladaptive brain plasticity that contributes to neuropathic pain after peripheral nerve degeneration.
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Fibromyalgia (FM) is characterized by widespread chronic pain, fatigue, and somatic symptoms. The influence of phenotypic changes in monocytes on symptoms associated with FM is not fully understood. The primary aim of this study was to take a comprehensive whole-body to molecular approach in characterizing relationships between monocyte phenotype and FM symptoms in relevant clinical populations. ⋯ Taken together, our data suggest that monocyte phenotype and their cytokine profiles are associated with pain-related symptoms in individuals with FM. Furthermore, our data show that IL-5 has a potential role in analgesia in an animal model of FM. Thus, targeting anti-inflammatory cytokines such as IL-5 secreted by circulating leukocytes could serve as a promising intervention to control pain and other somatic symptoms associated with FM.
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Diabetes is a leading cause of peripheral neuropathy (diabetic peripheral neuropathy, DPN), and uncontrolled long-lasting hyperglycemia leads to severe complications. A major proportion of diabetics develop excruciating pain with a variable course. Mechanisms leading to painful DPN are not completely understood and treatment options limited. ⋯ Our analyses identify miR-33 and miR-380 expressed in nociceptive neurons as critical denominators of diabetic pain and miR-124-1 as a mediator of physiological nociception. Our comprehensive analyses on the putative mRNA targets for miR-33 or miR-124-1 identified a set of mRNAs that are regulated after miR-33 or miR-124-1 overexpression in dorsal root ganglia in vivo. Our results shed light on the regulation of DPN pathophysiology and implicate specific miRNAs as novel therapeutic targets for treating painful DPN.