Rationale: Cancer patients receiving the antineoplastic drug paclitaxel report higher incidences and longer duration of treatment-resistant depression than patients receiving other classes of chemotherapeutics. Rodents treated with paclitaxel exhibit a suite of changes in affect-like behaviors. Further, paclitaxel causes chemotherapy-induced peripheral neuropathy (CIPN) in humans and rodents. Kappa opioid receptors (KOR) have a well-established role in depression and neuropathy. The contributions of KOR signaling to paclitaxel-induced aversive-like state and CIPN in rodents remain to be explored.
Objectives: We aimed to investigate whether dysregulation of the KOR/dynorphin system is associated with paclitaxel-mediated pain-like behavior and depression-like behavior.
Methods: Cancer-free male C57BL/6J mice were treated with four injections of vehicle or paclitaxel (32 mg/kg cumulative). The effects of the selective KOR antagonist norbinaltorphimine (norBNI) on paclitaxel-induced sucrose preference deficits and mechanical hypersensitivity were measured. Prodynorphin mRNA and receptor-mediated G protein activation were measured at two time points following the last paclitaxel injection using quantitative real-time polymerase chain reaction and agonist-stimulated [35S]guanosine-5'-O'-(γ-thio)-triphosphate ([35S]GTPγS) binding, respectively, in the nucleus accumbens (NAc), caudate-putamen, amygdala, and spinal cord.
Results: Paclitaxel produced a norBNI-reversible sucrose preference deficit, whereas mechanical hypersensitivity was not reversed by norBNI. Paclitaxel treatment increased the levels of mRNA for prodynorphin, a precursor for endogenous KOR agonists, in the NAc. Paclitaxel also had time-dependent effects on KOR-mediated G protein activation in the NAc.
Conclusions: These results suggest that KOR signaling mediates an initial aversive component of paclitaxel, but not necessarily paclitaxel-induced mechanical hypersensitivity.
Keywords: Anhedonia; Aversion; Chemotherapy-induced peripheral neuropathy; Dynorphin; Kappa opioid receptor; Nucleus accumbens; Paclitaxel; Pain; Two-bottle choice.