The Journal of neuroscience : the official journal of the Society for Neuroscience
-
Interleukin (IL)-1β and IL-18 play critical roles in the induction of chronic pain hypersensitivity. Their inactive forms are activated by caspase-1. However, little is known about the mechanism underlying the activation of pro-caspase-1. ⋯ Moreover, the IL-1β expression in spinal microglia and the induction of tactile allodynia following the intrathecal administration of CGA depended on CatB, whereas those induced by the intrathecal administration of ATP or lysophosphatidic acid were CatB independent. These results strongly suggest that CatB is an essential enzyme for the induction of chronic inflammatory pain through its activation of pro-caspase-1, which subsequently induces the maturation and secretion of IL-1β and IL-18 by spinal microglia. Therefore, CatB-specific inhibitors may represent a useful new strategy for treating inflammation-associated pain.
-
Studies with animal models have suggested that reaction of glia, including microglia and astrocytes, critically contributes to the development and maintenance of chronic pain. However, the involvement of glial reaction in human chronic pain is unclear. We performed analyses to compare the glial reaction profiles in the spinal dorsal horn (SDH) from three cohorts of sex- and age-matched human postmortem tissues: (1) HIV-negative patients, (2) HIV-positive patients without chronic pain, and (3) HIV patients with chronic pain. ⋯ In addition, proinflammatory cytokines, TNFα and IL-1β, were specifically increased in the SDH of pain-positive HIV patients. Furthermore, proteins in the MAPK signaling pathway, including pERK, pCREB and c-Fos, were also upregulated in the SDH of pain-positive HIV patients. Our findings suggest that reaction of astrocytes in the SDH may play a role during the maintenance phase of HIV-associated chronic pain.
-
Spontaneous activity in the developing brain contributes to its maturation, but how this activity is coordinated between distinct cortical regions and whether it might reflect developing sensory circuits is not well understood. Here, we address this question by imaging the spread and synchronization of cortical activity using voltage-sensitive dyes (VSDs) in the developing rat in vivo. In postnatal day 4-6 rats (n = 10), we collected spontaneous changes in VSD signal that reflect underlying membrane potential changes over a large craniotomy (50 mm2) that encompassed both the sensory and motor cortices of both hemispheres. ⋯ This activity also spread asymmetrically, toward the midline of the brain. We found that the spatial and temporal structure of such spontaneous cortical bursts closely matched that of sensory-evoked activity elicited via direct stimulation of the periphery. These data suggest that spontaneous cortical activity provides a recurring template of functional cortical circuits within the developing cortex and could contribute to the maturation of integrative connections between sensory and motor cortices.
-
Marked hypersensitivity to heat and mechanical (pressure) stimuli develop after a burn injury, but the neural mechanisms underlying these effects are poorly understood. In this study, we establish a new mouse model of focal second-degree burn injury to investigate the molecular and cellular basis for burn injury-induced pain. This model features robust injury-induced behavioral effects and tissue-specific altered cytokine profile, but absence of glial activation in spinal dorsal horn. ⋯ Furthermore, burn injury increases density and shifts activation of tetrodotoxin-sensitive currents in a hyperpolarized direction, both pro-excitatory properties, in DRG neurons from wild-type but not Na(v)1.7 cKO mice. We propose that, in sensory neurons damaged by burn injury to the hindpaw, Na(v)1.7 currents contribute to the hyperexcitability of sensory neurons, their communication with postsynaptic spinal pain pathways, and behavioral thresholds to heat stimuli. Our results offer insights into the molecular and cellular mechanisms of modality-specific pain signaling, and suggest Na(v)1.7-blocking drugs may be effective in burn patients.
-
Astrocytes and microglia become reactive under most brain pathological conditions, making this neuroinflammation process a surrogate marker of neuronal dysfunction. Neuroinflammation is associated with increased levels of translocator protein 18 kDa (TSPO) and binding sites for TSPO ligands. Positron emission tomography (PET) imaging of TSPO is thus commonly used to monitor neuroinflammation in preclinical and clinical studies. ⋯ TSPO mRNA levels were significantly increased, and TSPO protein was overexpressed by CNTF-activated astrocytes. We show that reactive astrocytes overexpress TSPO, yielding to a significant and selective binding of TSPO radioligands. Therefore, caution must be used when interpreting TSPO PET imaging in animals or patients because reactive astrocytes can contribute to the signal in addition to reactive microglia.