Abstract
Cold hypersensitivity is commonly associated with peripheral neuropathies but remains largely untreated due to limited understanding of its neurobiological mechanisms. Here we identify a role for kappa opioid receptors (KOR) in driving cold hypersensitivity. First, we show that systemic activation of KOR by the agonist U50,488 (U50), increases the latency to jump and the number of jumps on a cold plate at 3°C. Likewise, NorBNI, a KOR antagonist, attenuates U50-induced cold hypersensitivity. However, central administration of NorBNI does not block U50-induced cold hypersensitivity, suggesting that peripheral KORs may modulate this effect. To directly test this hypothesis, we use the peripherally-restricted KOR agonist, ff(nle)r-NH2 to demonstrate that selective activation of peripheral KOR is sufficient to induce 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 noxious cold sensation, in dorsal root ganglia (DRG) sensory neurons. Using fluorescent in situ hybridization, we show that KOR mRNA colocalizes with the transcripts for the cold-activated TRPA1 channels in DRG. Furthermore, U50 potentiates DRG intracellular calcium release during the simultaneous application of the TRPA1 agonist, mustard oil (MO). Together our data suggest that peripheral KORs may induce cold hypersensitivity by enhancing TRPA1 activation. These studies position the KOR system as an important modulator of cold sensation, offering a new potential point of intervention for reducing cold hypersensitivity.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
All figures have been reformatted and the text has been revised. Figure 1 now includes thermal imaging data, Figure 3 has more detailed co-localization analysis, Figure 4 added a U50 only condition.