Peripheral kappa opioid receptor activation drives cold hypersensitivity in mice

Noxious cold sensation is commonly associated with peripheral neuropathies, however, there has been limited progress in understanding the mechanism of cold pain. Here we identify a role for kappa opioid receptors (KOR) in driving cold hypersensitivity. First, we show that systemic activation of KOR by U50,488 (U50), increases the latency to jump and the number of jumps on a cold plate at 3°C. KOR antagonist, NorBNI, attenuates U50-induced cold hypersensitivity. However, the central administration of NorBNI does not block U50-induced cold hypersensitivity suggesting that peripheral KORs may modulate this effect. To directly test this, we use the peripherally-restricted KOR agonist, ff(nle)r-NH2 and also show cold hypersensitivity. To begin to understand how peripheral KORs drive cold hypersensitivity we investigated whether KORs interact with transient receptor potential ankyrin 1(TRPA1) channels, known to facilitate the perception of noxious cold, in dorsal root ganglion (DRG). Using fluorescent in situ hybridization, we show that KOR mRNA colocalizes with the transcripts for the cold-activated TRPA1 channels in DRG. We also show a potentiation in intracellular calcium release in DRG during the simultaneous application of the TRPA1 agonist, mustard oil (MO), and a KOR agonist, U50, when compared to MO alone. Together our data suggest that peripheral KORs may induce cold hypersensitivity through modulation of TRPA1 channels.