Peripheral kappa opioid receptors modulate cold hypersensitivity in a mouse model of chemotherapy-induced neuropathy

Noxious cold sensation is commonly associated with peripheral neuropathies; however, there has been limited progress in understanding the mechanism. Here, we identify a novel role for peripherally expressed kappa opioid receptors [KORs] in noxious cold hypersensitivity in a mouse model of chemotherapy. In this model, we show that oxaliplatin-induced cold hypersensitivity is attenuated using norbinaltorphimine (NorBNI, KOR antagonist (10 mg/kg, i.p.) in both male and female mice. To further examine the role of KORs in cold hypersensitivity, we show that activation of KOR with U50,488 (KOR agonist, 5 mg/kg i.p.) significantly increases the number of jumps on a cold plate at 3°C as compared to controls, which is attenuated by KOR antagonist NorBNI. We have determined that this effect is mediated through peripheral KORs using both pharmacology and a peripherally restricted KOR agonist, ff(nle)r-NH2. Using a conditional knockout mouse model of KOR in the dorsal root ganglia (using PirtCre;Oprkfl/fl), we see reduced U50488-induced noxious cold hypersensitivity as compared to controls in male and female mice, confirming the role of KORs in the dorsal root ganglia in mediating cold hypersensitivity. To confirm the role of peripheral KORs in oxaliplatin-induced cold allodynia, we use the PirtCre;Oprkfl/fl in our oxaliplatin-induced cold allodynia model. Here, we show that in the absence of KORs in dorsal root ganglia, oxaliplatin-induced cold hypersensitivity is attenuated in male and female mice. Overall, our data suggest that peripheral KORs modulate cold hypersensitivity in a mouse model of chemotherapy.