GnRH peripherally modulates nociceptor functions, exacerbating mechanical pain.

The function of peripheral nociceptors, the neurons that relay pain signals to the brain, are frequently tuned by local and systemic modulator substances. In this context, neurohormonal effects are emerging as an important modulatory mechanism, but many aspects remain to be elucidated. Here we report that gonadotropin-releasing hormone (GnRH), a brain-specific neurohormone, can aggravate pain by acting on nociceptors in mice. GnRH and GnRHR, the receptor for GnRH, are expressed in a nociceptor subpopulation. Administration of GnRH and its analogue, localized for selectively affecting the peripheral neurons, deteriorated mechanical pain, which was reproducible in neuropathic conditions. Nociceptor function was promoted by GnRH treatment in vitro, which appears to involve specific sensory transient receptor potential ion channels. These data suggest that peripheral GnRH can positively modulate nociceptor activities in its receptor-specific manner, contributing to pain exacerbation. Our study indicates that GnRH plays an important role in neurohormonal pain modulation via a peripheral mechanism.

Gpr83 Tunes Nociceptor Function, Controlling Pain.

The function of peripheral nociceptors is frequently tuned by the action of G protein-coupled receptors (GPRs) that are expressed in them, which contribute to pain alteration. Expanding new information on such GPRs and predicting their potential outcomes can help to construct new analgesic strategies based on their modulations. In this context, we attempted to present a new GPR not yet acknowledged for its pain association. Gpr83 exhibits relatively high expressions in the peripheral nervous system compared to other tissues when we mined and reconstructed Gene Expression Omnibus (GEO) metadata, which we confirmed using immunohistochemistry on murine dorsal root ganglia (DRG). When Gpr83 expression was silenced in DRG, neuronal and behavioral nociception were all downregulated. Pathologic pain in hind paw inflammation and chemotherapy-induced peripheral neuropathy were also alleviated by this Gpr83 knockdown. Dependent on exposure time, the application of a known endogenous Gpr83 ligand PEN showed differential effects on nociceptor responses in vitro. Localized PEN administration mitigated pain in vivo, probably following Gq/11-involved GPR downregulation caused by the relatively constant exposure. Collectively, this study suggests that Gpr83 action contributes to the tuning of peripheral pain sensitivity and thus indicates that Gpr83 can be among the potential GPR targets for pain modulation.

Diagnostic performance of a minimized protocol of non-contrast MRI for hepatocellular carcinoma surveillance.

PURPOSE: To evaluate the per-patient diagnostic performance of a minimized non-contrast MRI protocol for hepatocellular carcinoma (HCC) surveillance in cirrhotic liver, as well as factors affecting diagnostic sensitivity. METHODS: A total of 226 patients who underwent MRI for HCC surveillance over an 8 year period were included in this retrospective study. Set1 consisted of diffusion-weighted imaging and respiratory-triggered, fast-spin echo T2-weighted imaging with fat suppression. Set2 included T1-weighted in/opposed-phase images added to the images from Set1. Image sets were scored as positive or negative for HCC according to predetermined criteria by two readers independently. The diagnostic performance of the two sets in conjunction with α-fetoprotein (AFP) was assessed and compared using the McNemar test. Logistic regression was used to determine factors that affected sensitivity. RESULTS: The sensitivity, specificity, and accuracy of Set1 of readers 1 and 2 were 84.4%/87.3%, 86.8%/86.8%, and 85.0%/87.2%, respectively; and those for Set2 were 87.3%/89.6%, 81.1%/79.2%, and 85.8/87.2%, respectively. The sensitivities of the sets were not significantly different (p = 0.063). Sensitivities of both sets in conjunction with AFP were higher than those of MRI alone without statistical significance (87.3%/89.6%, p = 0.063/> 0.99; 89.6%/89.6%, p = 0.125/> 0.99). In very early-stage HCC, the sensitivities of Sets1 and 2 were 73.1%/76.9% and 76.9%/82.7%, respectively. Perihepatic ascites and size less than 2 cm were associated with sensitivity (p < 0.05). CONCLUSIONS: A minimized non-contrast MRI protocol consisting of Fat-sat T2WI and DWI is highly sensitive and may be a viable method for HCC surveillance of the cirrhotic liver. The inclusion of T1-weighted in/opposed-phase and AFP may increase this sensitivity.