Pain
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Neurofibromatosis type 1 (NF1), a genetic disorder linked to inactivating mutations or a homozygous deletion of the Nf1 gene, is characterized by tumorigenesis, cognitive dysfunction, seizures, migraine, and pain. Omic studies on human NF1 tissues identified an increase in the expression of collapsin response mediator protein 2 (CRMP2), a cytosolic protein reported to regulate the trafficking and activity of presynaptic N-type voltage-gated calcium (Cav2.2) channels. Because neurofibromin, the protein product of the Nf1 gene, binds to and inhibits CRMP2, the neurofibromin-CRMP2 signaling cascade will likely affect Ca channel activity and regulate nociceptive neurotransmission and in vivo responses to noxious stimulation. ⋯ Stimulus-evoked release of calcitonin gene-related peptide from lumbar spinal cord slices was inhibited by t-CNRP1. Intrathecal administration of t-CNRP1 was antinociceptive in experimental models of inflammatory, postsurgical, and neuropathic pain. Our results demonstrate the utility of t-CNRP1 to inhibit CRMP2 protein-protein interactions for the potential treatment of pain.
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Primary dysmenorrhea (PD), or painful menstruation in the absence of identified uterine pathology, affects 5 to 9 in every 10 reproductive-aged women. Despite its high prevalence, just a few studies with very small patient numbers have focused on health-related quality of life impairment in PD. We aimed to assess health-related quality of life values for a severe and a mild hypothetical PD health state using 10-year time trade-off and willingness-to-pay methods. ⋯ Compared with the non-PD group, women with PD valued both health states worse according to willingness to pay (P < 0.05) but similar in the time trade-off. It seems that PD substantially contributes to the quality-adjusted life year loss in this age group, which is comparable with losses from chronic diseases such as type 1 diabetes, asthma, atopic eczema, or chronic migraine. Our findings provide a useful input to cost-effectiveness and cost-benefit analyses of PD treatments.
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Oral Bulleyaconitine A (BLA) is effective for treating neuropathic pain in human patients, but the underlying mechanism is poorly understood. Here, we tested whether BLA blocked voltage-gated sodium channels (VGSCs) in dorsal root ganglion (DRG) neurons. Compelling evidence shows that voltage-gated sodium channels are upregulated in uninjured DRG neurons but downregulated in injured ones following peripheral nerve injury. ⋯ The upregulation of protein kinase C was associated with the preferable effect of BLA on TTX-S Na channels in the uninjured DRG neurons. Local application of BLA onto L4-6 DRGs at 0.1 to 10 nM dose-dependently alleviated the mechanical allodynia and thermal hyperalgesia in L5 spinal nerve ligation model. Thus, preferable blockage of TTX-S Na channels in uninjured DRG neurons may contribute to BLA's antineuropathic pain effect.
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Lysophosphatidic acid (LPA) is a bioactive lipid that impacts neurological outcomes after neurotrauma by inhibiting neuroregeneration, promoting inflammation, and contributing to behavioral deficits. Blocking LPA signaling with a novel anti-LPA monoclonal antibody (mAb) is neuroprotective after traumatic brain injury (TBI) if given to injured animals whose blood-brain barrier (BBB) has been compromised. It is hypothesized that the anti-LPA mAb could improve chronic pain initiated by TBI. ⋯ Compared with control rats that received LT3114 but no TBI, TBI rats demonstrated significantly higher concentrations of intranasally administered LT3114 antibody in some tissues. In behavioral studies, a significant attenuation of mechanical allodynia after TBI was observed in the anti-LPA treatment group (P = 0.0079), when compared with vehicle controls within 14 days after TBI. These results suggest that intranasal application of the anti-LPA antibody directly accesses CNS sites involved in TBI-related pain and that this access attenuates pain sequelae to the neurotrauma.
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Psoriasis is often accompanied by itch, but the mechanisms behind this symptom remain elusive. Dynamic changes in epidermal innervation have been observed under chronic itch conditions. Therefore, we investigated whether epidermal innervation is altered in the imiquimod-induced psoriasis mouse model, whether blockade of neurotrophic growth factor signaling can reduce these changes, and whether this system can impact psoriatic itch. ⋯ Treatment of imiquimod-challenged mice with an NRTN-neutralizing antibody significantly reduced nonpeptidergic nerve density as well as spontaneous scratching. These results indicate that NRTN contributes to an increase in the epidermal density of nonpeptidergic nerves in the imiquimod-induced psoriasis model, and this increase may be a factor in chronic itch for these mice. Therefore, inhibition of NRTN could be a potential treatment for chronic itch in psoriasis.