Antinociceptive effects of intrathecal Neuropeptide B/W receptor 1 agonists in mouse acute nociception, peripheral neuropathy, and inflammatory pain models.

Background: The Neuropeptide B/W Receptor 1 (NPBWR1) system, including its two endogenous ligands, Neuropeptides B and W (NPB and NPW), has garnered interest as potential target to develop novel analgesics. Behavioral studies were typically conducted with exogenously administered endogenous ligands. In this study, we examined truncated NPB-23 and its peptidomimetic RTIBW-16 in a panel of antinociceptive assays including the hot plate, carrageenan-induced inflammatory, and paclitaxel chemotherapy-induced peripheral neuropathy (CIPN) pain assays. Methods: Male and female C57BL/6 mice underwent testing in the hot plate acute nociception assay. After a minimum one-week washout, mice were enrolled in the carrageenan inflammatory pain model, receiving intraplanar carrageenan (0.3% carrageenan in a 20 μL). Separate mouse cohorts received a cycle of intraperitoneal paclitaxel injections (cumulative dose 32 mg/kg). The von Frey assay was utilized to assess CIPN and carrageenan-induced allodynia. Results: NPB-23 and RTIBW-16 dose-dependently produced thermal antinociception, attenuated CIPN allodynia and carrageenan-induced allodynia with some differences regarding onset time, potency and duration of action. In the hot plate assay, RTIBW-16 showed earlier onset but shorter duration of action than NPB-23 with similar maximum peak effects. Both compounds were statistically equipotent in the reversal of mechanical allodynia induced by either paclitaxel or carrageenan. RTIBW-16 maintained a longer duration of action than NPB-23 in CIPN assay. Conclusions: Both NPBWR1 agonists alleviated thermal and inflammatory pain. Notably, we demonstrated for the first time that NPBWR1 agonists exhibited analgesic effect in the CIPN model. Our findings highlight NPBWR1 as a promising target for developing analgesics with novel mechanisms.