Piezo channels are mechanosensitive ion channels. Piezo1 is primarily expressed in nonsensory tissues, whereas Piezo2 is predominantly found in sensory tissues, including dorsal root ganglion (DRG) neurons. However, a recent study demonstrated the intracellular calcium response to Yoda1, a selective Piezo1 agonist, in trigeminal ganglion (TG) neurons. Herein, we investigate the expression of Piezo1 mRNA and protein in mouse and human DRG neurons and the activation of Piezo1 via calcium influx by Yoda1. Yoda1 induces inward currents mainly in small- (<25 μm) and medium-sized (25–35 μm) mouse DRG neurons. The Yoda1-induced Ca2+ response is inhibited by cationic channel blocker, ruthenium red and cationic mechanosensitive channel blocker, GsMTx4. To confirm the specific inhibition of Piezo1, we performed an adeno-associated virus serotype 2/5 (AAV2/5)-mediated delivery of short hairpin RNA (shRNA) into mouse DRG neurons. AAV2/5 transfection downregulates piezo1 mRNA expression and reduces Ca2+ response by Yoda1. Piezo1 also shows physiological functions with transient receptor potential vanilloid 1 (TRPV1) in the same DRG neurons and is regulated by the activation of TRPV1 in mouse DRG sensory neurons. Overall, we found that Piezo1 has physiological functions in DRG neurons and that TRPV1 activation inhibits an inward current induced by Yoda1.

Neuropathic pain (NP) is a complex, debilitating, chronic pain state, heterogeneous in nature and caused by a lesion or disease affecting the somatosensory system. Its pathogenesis involves a wide range of molecular pathways. NP treatment is extremely challenging, due to its complex underlying disease mechanisms. Current pharmacological and nonpharmacological approaches can provide long-lasting pain relief to a limited percentage of patients and lack safe and effective treatment options. Therefore, scientists are focusing on the introduction of novel treatment approaches, such as stem cell therapy. A growing number of reports have highlighted the potential of stem cells for treating NP. In this review, we briefly introduce NP, current pharmacological and nonpharmacological treatments, and preclinical studies of stem cells to treat NP. In addition, we summarize stem cell mechanisms—including neuromodulation in treating NP. Literature searches were conducted using PubMed to provide an overview of the neuroprotective effects of stem cells with particular emphasis on recent translational research regarding stem cell-based treatment of NP, highlighting its potential as a novel therapeutic approach.

The transient receptor potential vanilloid 1 (TRPV1) ion channel plays an important role in the peripheral nociceptive pathway. TRPV1 is a polymodal receptor that can be activated by multiple types of ligands and painful stimuli, such as noxious heat and protons, and contributes to various acute and chronic pain conditions. Therefore, TRPV1 is emerging as a novel therapeutic target for the treatment of various pain conditions. Notably, various peptides isolated from venomous animals potently and selectively control the activation and inhibition of TRPV1 by binding to its outer pore region. This review will focus on the mechanisms by which venom-derived peptides interact with this portion of TRPV1 to control receptor functions and how these mechanisms can drive the development of new types of analgesics.

Diosgenin is a botanical steroidal saponin with immunomodulatory, anti-inflammatory, anti-oxidative, anti-thrombotic, anti-apoptotic, anti-depressant, and anti-nociceptive effects. However, the effects of diosgenin on anti-nociception are unclear. Transient receptor potential vanilloid 1 (TRPV1) plays an important role in nociception. Therefore, we investigated whether TRPV1 antagonism mediates the anti-nociceptive effects of diosgenin. In vivo mouse experiments were performed to examine nociception-related behavior, while in vitro experiments were performed to examine calcium currents in dorsal root ganglion (DRG) and Chinese hamster ovary (CHO) cells. The duration of capsaicin-induced licking (pain behavior) was significantly reduced following oral and intraplantar administration of diosgenin, approaching levels observed in mice treated with the TRPV1 antagonist N-(4-tertiarybutylphenyl)-4-(3-cholorphyridin-2-yl) tetrahydropyrazine-1(2H)-carbox-amide. Additionally, oral administration of diosgenin blocked capsaicin-induced thermal hyperalgesia. Further, diosgenin reduced capsaicin-induced Ca2+ currents in a dose-dependent manner in both DRG and CHO cells. Oral administration of diosgenin also improved thermal and mechanical hyperalgesia in the sciatic nerve constriction injury-induced chronic pain model by reducing the expression of TRPV1 and inflammatory cytokines in DRG cells. Collectively, our results suggest that diosgenin exerts analgesic effects via antagonism of TRPV1 and suppression of inflammation in the DRG in a mouse model of neuropathic pain.

Epidural and intrathecal routes are the most effective drug administration methods for pain management in clinical and experimental medicine to achieve quick results, reduce required drug dosages, and overcome the adverse effects associated with the oral and parenteral routes. Beyond pain management with analgesics, the intrathecal route is more widely used for stem cell therapy, gene therapy, insulin delivery, protein therapy, and drug therapy with agonist, antagonist, or antibiotic drugs in experimental medicine. However, clear information regarding intrathecal and epidural drug delivery in rats and mice is lacking, despite differences from human medicine in terms of anatomical space and proximity to the route of entry. In this study, we discussed and compared the anatomical locations of the epidural and intrathecal spaces, cerebrospinal fluid volume, dorsal root ganglion, techniques and challenges of epidural and intrathecal injections, dosage and volume of drugs, needle and catheter sizes, and the purpose and applications of these two routes in different disease models in rats and mice. We also described intrathecal injection in relation to the dorsal root ganglion. The accumulated information about the epidural and intrathecal delivery routes could contribute to better safety, quality, and reliability in experimental research.