Psoriasis is inflammatory skin disease associated with itch, a troublesome symptom with few therapeutic options. Transient receptor potential channel 4 (TRPC4) is highly expressed in dorsal root ganglia (DRGs). Recently, we have revealed a previously unknown itch signaling in DRG neurons by which TRPC4 mediates itch to serotonergic antidepressants, and demonstrated the antipruritic effect of the TRPC4 inhibitor ML204. However, the role of TRPC4 in acute and chronic itch is still largely unknown. Here, we have characterized the expression of TRPC4 in peptidergic DRG neurons and showed that acute itch induced by serotonin and histamine was attenuated in TRPC4 knockout (TRPC4 KO) mice and mice treated with ML204. We also showed that silencing TRPC4 in DRG and its inhibition by intradermal injections were also effective in decreasing psoriatic itch after repeated applications of imiquimod (IMQ), a preclinical model of psoriasis. Of clinical relevance, intradermal injections of ML204 in psoriasiform skin significantly reversed IMQ-established chronic itch and cutaneous inflammation. Given that TRPC4 is expressed in human DRGs and a specific inhibitor is in clinical trials, our data not only expand our understanding of itch and psoriasis, but also reveal TRPC4 as a potential therapeutic target with considerable translational benefit.

Reactor internals are sensitive to dynamic loads such as earthquakes and flow induced vibration. Thus, it is essential to identify the dynamic characteristics to evaluate the seismic integrity of the structures. However, a full-sized system is too large to perform modal experiments, making it difficult to extract data on its modal characteristics. In this research, we constructed a finite element model of the APR1400 reactor internals to identify their modal characteristics. The commercial reactor was selected to reflect the actual boundary conditions. Our FE model was constructed based on scale-similarity analysis and fluid-structure interaction investigations using a fabricated scaled-down model

Modulation of the function of somatosensory neurons is an important analgesic strategy, requiring the proposal of novel molecular targets. Many G-protein-coupled receptors (GPRs) have been deorphanized, but the receptor locations, outcomes due to their activations, and their signal transductions remain to be elucidated, regarding the somatosensory nociceptor function. Here we report that GPR171, expressed in a nociceptor subpopulation, attenuated pain signals via Gi/o-coupled modulation of the activities of nociceptive ion channels when activated by its newly found ligands. Administration of its natural peptide ligand and a synthetic chemical ligand alleviated nociceptor-mediated acute pain aggravations and also relieved pathologic pain at nanomolar and micromolar ranges. This study suggests that functional alteration of the nociceptor neurons by GPR171 signaling results in pain alleviation and indicates that GPR171 is a promising molecular target for peripheral pain modulation.

Cyclooxygenase metabolizes dihomo-γ-linolenic acid and arachidonic acid to form prostaglandin (PG) E, including PGE1 and PGE2, respectively. Although PGE2 is well known to play an important role in the development and maintenance of hyperalgesia and allodynia, the role of PGE1 in pain is unknown. We confirm whether PGE1 induced pain using orofacial pain behavioral test in mice and determine the target molecule of PGE1 in TG neurons with whole-cell patch-clamp and immunohistochemistry. Intradermal injection of PGE1 to the whisker pads of mice induced a reduced threshold, enhancing the excitability of HCN channel-expressing trigeminal ganglion (TG) neurons. The HCN channel-generated inward current (I_h) was increased by 135.3 ± 4.8% at 100 nM of PGE1 in small- or medium-sized TG, and the action of PGE1 on I_h showed a concentration-dependent effect, with a median effective dose (ED₅₀) of 29.3 nM. Adenylyl cyclase inhibitor (MDL12330A), 8-bromo-cAMP, and the EP2 receptor antagonist AH6809 inhibited PGE1-induced I_h. Additionally, PGE1-induced mechanical allodynia was blocked by CsCl and AH6809. PGE1 plays a role in mechanical allodynia through HCN2 channel facilitation via the EP2 receptor in nociceptive neurons, suggesting a potential therapeutic target in that PGE1 could be involved in pain as endogenous substances under inflammatory conditions.