Metabotropic glutamate receptor 5-mediated inhibition of inward-rectifying K+ channel 4.1 contributes to orofacial ectopic mechanical allodynia following inferior alveolar nerve transection in male mice.

Inward-rectifying K+ channel 4.1 (Kir4.1), which regulates the electrophysiological properties of neurons and glia by affecting K+ homeostasis, plays a critical role in neuropathic pain. Metabotropic glutamate receptor 5 (mGluR5) regulates the expression of Kir4.1 in retinal Müller cells. However, the role of Kir4.1 and its expressional regulatory mechanisms underlying orofacial ectopic allodynia remain unclear. This study aimed to investigate the biological roles of Kir4.1 and mGluR5 in the trigeminal ganglion (TG) in orofacial ectopic mechanical allodynia and the role of mGluR5 in Kir4.1 regulation. An animal model of nerve injury was established via inferior alveolar nerve transection (IANX) in male C57BL/6J mice. Behavioral tests indicated that mechanical allodynia in the ipsilateral whisker pad lasted at least 14 days after IANX surgery and was alleviated by the overexpression of Kir4.1 in the TG, as well as intraganglionic injection of an mGluR5 antagonist (MPEP hydrochloride) or a protein kinase C (PKC) inhibitor (chelerythrine chloride); Conditional knockdown of the Kir4.1 gene downregulated mechanical thresholds in the whisker pad. Double immunostaining revealed that Kir4.1 and mGluR5 were co-expressed in satellite glial cells in the TG. IANX downregulated Kir4.1 and upregulated mGluR5 and phosphorylated PKC (p-PKC) in the TG; Inhibition of mGluR5 reversed the changes in Kir4.1 and p-PKC that were induced by IANX; Inhibition of PKC activation reversed the downregulation of Kir4.1 expression caused by IANX (p < .05). In conclusion, activation of mGluR5 in the TG after IANX contributed to orofacial ectopic mechanical allodynia by suppressing Kir4.1 via the PKC signaling pathway.

Influencing Factors of Health Technology Assessment to Orphan Drugs: Empirical Evidence in England, Scotland, Canada, and Australia.

This study summarizes the intrinsic criteria for the recommendation of orphan drugs in England, Scotland, Canada, and Australia with the aim of understanding the rationale for the variability in decision-making and to provide a reference for the establishment of criteria in the process of access to health insurance for orphan drugs in different countries and the construction of national uniform criteria. A comparative analysis of 60 health technology assessment (HTA) guidelines of 15 drug-indication pairs appraised by four countries (England, Scotland, Canada, and Australia) from 2017 to 2018 was done, including an in-depth analysis of a case study. Agreement levels were measured using kappa scores. Associations were explored through correspondence analysis. The four countries possess some homogeneity in the assessment, but each has its own preferences. Poor agreement exists between England, Scotland, and Canada (-0.41 < kappa score < 0.192). In the correspondence analysis, England placed more emphasis on treatment methods in terms of control type when making recommendations. Canada and Scotland focused more on trial type with Canada placing more emphasis on phase III and open-label trials and on cost-utility analysis, while Australia was less studied in terms of economic models. Different countries have different goals when establishing HTA decisions for orphan drugs due to their different degrees of orphan drug coverage. Different countries should not only combine their unique values of clinical benefit and cost-effectiveness in the assessment of orphan drugs but also give different weights during the HTA process, after considering account the development of the country itself.