Kappa opioid receptors mediate an initial aversive component of paclitaxel-induced neuropathy
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ORIGINAL INVESTIGATION
Kappa opioid receptors mediate an initial aversive component of paclitaxel-induced neuropathy Julie A. Meade 1 M. I. Damaj 1,3
&
Y. Alkhlaif 1 & K. M. Contreras 1 & S. Obeng 2 & W. Toma 1 & L. J. Sim-Selley 1 & D. E. Selley 1 &
Received: 11 December 2019 / Accepted: 29 May 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Rationale Cancer patients receiving the antineoplastic drug paclitaxel report higher incidences and longer duration of treatmentresistant 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 agoniststimulated [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 Paclitaxel . Chemotherapy-induced peripheral neuropathy . Pain . Kappa opioid receptor . Dynorphin . Aversion . Anhedonia . Two-bottle choice . Nucleus accumbens
Introduction With advances in cancer treatment, the 10-year survival rates have increased to 83.1% as of 2014 (DeSantis et al. 2014),
* Julie A. Meade [email protected] 1
Department of Pharmacology and Toxicology, Virginia Commonwealth University, Medical College of Virginia Campus, Box 980613, Richmond, VA 23298-0613, USA
2
Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA
3
Translational Research Initiative for Pain and Neuropathy, Virginia Commonwealth University, Richmond, VA 23298, US
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