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

Abstract

<h4>Background</h4>The neuropeptide B/W receptor 1 (NPBWR1) system, including its two endogenous ligands, Neuropeptides B and W (NPB and NPW), has garnered interest as a 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.<h4>Methods</h4>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 volume). 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 (0.56-100 µg) were administered via acute intrathecal (it) injections.<h4>Results</h4>Single it doses of NPB-23 and RTIBW-16 evoked dose-dependent antinociception (hotplate) and evoked dose-dependent anti-allodynia in mouse models of CIPN and carrageenan-induced unilateral hind paw inflammation. In the hot plate assay, RTIBW-16 showed an 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 the CIPN assay.<h4>Conclusions</h4>Single it doses of both NPBWR1 agonists alleviated acute pain in the hotplate test and mechanical allodynia in the hind paws of a mouse model of inflammatory pain. NPBWRI agonists also evoked anti-allodynia in a mouse model of CIPN. Our findings suggest that NPBWR1 is a promising target for developing analgesics with novel mechanisms.