Peripheral Kappa Opioid Receptor Activation Drives Noxious Cold Hypersensitivity in Mice

Noxious cold sensation is associated with peripheral neuropathies, yet little is known about the mechanisms underlying cold hypersensitivity and pain. Here we identify a role for the kappa opioid receptor (KOR) system in driving cold hypersensitivity. The cold plate assay was used to determine the cold hypersensitivity in wildtype (WT) (C57BL/6J) and Transient receptor potential (TRP) Ankyrin –1(A1) KO mice. Fluorescent in-situ hybridization (FISH) assay was used to determine the expression of KOR in the dorsal root ganglion (DRG) and its co-expression with TRPA1 transcripts in mouse and human DRG's. Ex-vivo calcium imaging was used to investigate calcium dynamics between KOR and TRPA1 in the modulation of cold hypersensitivity in mouse DRG's. Activation of KOR by the agonist U50,488 (U50) increased the number of jumps on a cold plate at the noxious temperature of 3°C in WT mice. We show that this cold hypersensitivity is mediated by peripherally expressed KOR. To begin to explore how peripherally expressed KOR modulates cold hypersensitivity, using FISH, we found that KOR colocalized with TRPA1 transcripts in both mice (WT) and human DRG. Interestingly, KOR activation potentiated TRPA1-dependent calcium signaling in DRG neurons of WT mice. Furthermore, we show that KOR mediated cold hypersensitivity is attenuated in TRPA1-/- mice on cold plate at 3°C, suggesting that KOR mediated cold hypersensitivity might be through TRPA1. Together, we have identified a novel role for peripheral KOR activation in driving cold hypersensitivity, and this behavior is likely mediated through potentiated TRPA1 activity. We have identified a novel role for kappa opioid receptors (KOR) in driving cold hypersensitivity via TRPA1. These findings will have major implications not only in our understanding of cold sensitivity, but also the potential to open up alternative therapeutic targets to allow us to treat cold hypersensitivity and pain.