Assessment of an Allosteric Modulator of GIRK 1/2 in Preclinical Models of Cancer-Related Neuropathies to Alleviate Associated Mechanical Allodynia

Abstract ID 91703 Poster Board 477 Cancer patients commonly experience neuropathic pain caused by off-target effects of their chemotherapeutic treatments known as chemotherapy-induced peripheral neuropathy (CIPN), or by tumor metastasis to bone known as cancer-induced bone pain (CIBP). There are currently no treatments for either of these cancer-related neuropathies and current clinical regimens focus on symptom management. Current treatments have limited therapeutic windows due to negative side effects associated with utilized therapeutics that include opioids, anti-depressants, and gabapentinoids. A recently synthesized allosteric modulator of the g-protein activated inwardly rectifying potassium channels (GIRK) 1 and 2, known as GAT-1508, may be able to provide effective anti-allodynic effects with an improved therapeutic window. Utilizing CIPN and CIBP preclinical models, we assessed whether GAT-1508 would attenuate cancer-related mechanical allodynia. The CIPN model was induced in male and female C57BL/6 mice via a dosing cycle (8 mg/kg ip, given every other day, 32 mg/kg cumulative) of paclitaxel, a chemotherapeutic agent. The CIBP neuropathic pain model was induced in male and female C3H/HeJ mice, a mouse strain that is syngeneic to the murine fibrosarcoma cell line, NCTC-2472. Following implantation of NCTC-2472 fibrosarcoma cells into the calcaneus bone, mice exhibited mechanical allodynia associated with bone tumor metastasis. Vehicle injection served as a control and the von Frey assay was utilized to assess mechanical allodynia in both models. GAT-1508 (17.8–100 mg/kg, ip) dose-relatedly attenuated CIPN-induced mechanical allodynia (F (1.42, 21.36) = 485.6, p < 0.0001). Similarly, GAT-1508 dose-relatedly attenuated CIBP-induced mechanical allodynia (F 1.3, 9.1) = 22.64, p < 0.001). Additionally, at the highest dose tested (100 mg/kg, i.p.), GAT-1508 did not alter locomotor behavior, including distance (p = 0.71) and speed (p = 0.77). GAT-1508 dose-relatedly attenuated mechanical allodynia in both models. Given that no locomotor effects were observed, GAT-1508 may provide therapeutic effects with an improved therapeutic window and limited side-effects. Ultimately, these findings support further development and study of GIRK channel modulation for potential neuropathic pain therapeutics.