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

## TL;DR

This study shows that activating the NPBWR1 receptor can reduce different types of pain in mice, including chemotherapy-induced pain, suggesting a new target for pain treatments.

## Contribution

The study demonstrates for the first time that NPBWR1 agonists have analgesic effects in a chemotherapy-induced peripheral neuropathy model.

## Key findings

- NPBWR1 agonists NPB-23 and RTIBW-16 reduced thermal and inflammatory pain in mice.
- Both compounds effectively reversed mechanical allodynia caused by paclitaxel or carrageenan.
- RTIBW-16 showed faster onset and longer duration of action in some pain models compared to NPB-23.

## Abstract

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.

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.

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.

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.