Pain
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Microglial cells, the resident immune cells of the spinal cord, become activated in response to peripheral nerve injury. Microglia activation contributes to the development of neuropathic pain. Here we employed microarray analysis of individually collected pools of 10 spinal microglia cells to identify changes of levels and cell-to-cell expression variance of microglial genes during their activation after peripheral nerve injury. ⋯ Early POD1 microglia exhibited a very distinct expression profile compared to late POD7 microglia, possibly leading to the transition from initiation to maintenance of neuropathic pain. We found sample variance patterns that were consistent with the hypothesis that microglia were highly heterogeneous at the level of individual cells, and variation analysis identified 56 microglial genes potentially linked to the maintenance of neuropathic pain which included Gria1. This study provides insights into spinal microglial biology and reveals novel microglial targets for the treatment of neuropathic pain.
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Colonoscopy is an invaluable tool for the screening and diagnosis of many colonic diseases. For most colonoscopies, moderate sedation is used during the procedure. However, insufflation of the colon produces a nociceptive stimulus that is usually accompanied by facial grimacing/groaning while under sedation. ⋯ The pattern of the activation is similar to that previously observed during nociceptive stimuli in awake healthy individuals, suggesting that this approach may be used to evaluate brain activity evoked by nociceptive stimuli under sedation, when there is incomplete analgesia. Although some patients report recollection of procedural pain after the procedure, the effects of repeated nociceptive stimuli in surgical patients may contribute to postoperative changes including chronic pain. The results from this study indicate that NIRS may be a suitable technology for continuous nociceptive afferent monitoring in patients undergoing sedation and could have applications under sedation or anesthesia.
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Painful diabetic neuropathy is associated with impaired opioid analgesia; however, the precise mechanism in sensory neurons remains unclear. This study aimed to identify putative mechanisms involved in modified opioid responsiveness during early streptozotocin-induced diabetes in rats. In this study, we demonstrate that in diabetic animals, impaired peripheral opioid analgesia is associated with a reduction in functional mu-opioid receptor (MOR) G protein coupling. ⋯ Importantly, blocking PKC activation using PKC selective inhibitor, silencing RAGE with intrathecal RAGE siRNA, or inhibiting advanced glycation end product (AGE) formation prevented sensory neuron MOR phosphorylation and, consequently, restored MOR G protein coupling and analgesic efficacy. Thus, our findings give the first in vivo evidence of a RAGE-dependent PKC-mediated heterologous MOR phosphorylation and desensitization in sensory neurons under pathological conditions such as diabetic neuropathy. This may unravel putative mechanisms and suggest possible prevention strategies of impaired opioid responsiveness.
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Changes in the nerve's microenvironment and local inflammation resulting from peripheral nerve injury participate in nerve sensitization and neuropathic pain development. Taking part in these early changes, disruption of the blood-nerve barrier (BNB) allows for infiltration of immunocytes and promotes the neuroinflammation. However, molecular mechanisms engaged in vascular endothelial cells (VEC) dysfunction and BNB alterations remain unclear. ⋯ In vitro, activation of Toll-like receptor 4 in VEC downregulated the components of Hh pathway and altered the endothelial functional state. Inhibition of Hh signaling in the ScN of naive rats mimicked the biochemical and functional alterations observed after CCI and was, on its own, sufficient to evoke local neuroinflammation and sustained mechanical allodynia. Alteration of the Hh signaling pathway in VEC associated with peripheral nerve injury, is involved in BNB disruption and local inflammation, and could thus participate in the early changes leading to the peripheral nerve sensitization and, ultimately, neuropathic pain development.