Peripheral kappa opioid receptor activation drives noxious cold hypersensitivity in mice

Abstract

Noxious cold sensation is commonly associated with peripheral neuropathies, however, there has been limited progress in understanding the mechanism of cold pain. Transient receptor potential (TRP) A1 channels facilitate the perception of noxious cold at the level of dorsal root ganglia (DRG), where kappa opioid receptors (KOR) are also expressed but have not previously been implicated in cold sensation. Here we identify a new role for KOR in enhancing cold hypersensitivity. First, we show that systemic KOR agonism (U50,488, KOR agonist), significantly potentiates the latency to jump and the number of jumps on the cold plate compared controls at 3°C. Importantly, NorBNI (KOR antagonist) attenuates U50,488-induced cold hypersensitivity. However, the central administration of NorBNI does not block U50,488-induced cold hypersensitivity suggesting that peripheral KOR likely modulate this effect. Furthermore, the peripherally-restricted KOR agonist, ff(nle)r-NH2 also induces cold hypersensitivity. Using fluorescent in situ hybridization, we show that KOR mRNA colocalizes with the transcripts for the cold-activated TRPA1 and TRPM8 channels in DRG. Finally, using calcium imaging in DRG, we show that intracellular calcium release is potentiated during the simultaneous application of a TRPA1 agonist, mustard oil (MO), and a KOR agonist (U50,488), when compared to MO alone. This potentiated calcium response is absent in TRPA1 KO mice. Together our data suggest that KOR-induces cold hypersensitivity through modulation of peripheral TRPA1 channels. These findings indicate that whether activation of peripheral KOR is protective or not may be dependent on the pain modality.

The cannabinoid agonist CB-13 produces peripherally mediated analgesia in mice but elicits tolerance and signs of central nervous system activity with repeated dosing

“…The spinal column was removed and bisected; lumbar dorsal root ganglion (DRG) were removed and pooled, and subjected to enzymatic incubations as described. 18,56,83 Dorsal root ganglion tissue was incubated in papain (45 U in HBSS1H, Worthington) for 20 minutes at 37˚C, rinsed, and incubated in collagenase (1.5 mg/ mL in HBSS1H, Sigma-Aldrich) for 20 minutes. Dorsal root ganglion were washed again with HBSS1H, then transferred to 1 mL of DRG media, which consisted of Neurobasal A medium (Invitrogen) supplemented with 100 U/mL penicillin/streptomycin (Corning), 2 mM GlutaMAX (Life Technologies), 2% B27 (Gibco), and 5% fetal bovine serum (Gibco).…”

Perinatal Oxycodone Exposure Causes Long Term Sex-Dependent Changes in Sensory and Reward Processing in Adult Mice

“…We see no differences in thermal sensitivity in the male mice tested. The altered sensory perception in the Long Oxy females is consistent with KOR activation, which has been implicated in enhancing cold sensitivity while also demonstrating antinociceptive properties toward noxious heat stimuli 21 . Our findings are the first to demonstrate sex-specific long-term sensory processing alterations following prolonged Oxy exposure in female offspring.…”

“…The hot/cold plate assay was used to determined changes in thermal pain thresholds between the mice as previously described 21 . Briefly, mice were habituated in the testing room for 30 minutes prior to the hot/cold plate assays.…”

The cannabinoid agonist CB-13 produces peripherally mediated analgesia in mice but elicits tolerance and signs of CNS activity with repeated dosing

“…For each tissue preparation, mice were euthanized via induction of isoflurane briefly followed by decapitation. The spinal column was removed and bisected; lumbar DRG were removed and pooled, and subjected to enzymatic incubations as described [16,45,66]. DRG tissue was incubated in papain (45 U in HBSS+H, Worthington) for 20 min at 37°C, rinsed, and incubated in collagenase (1.5 mg/mL in HBSS+H, Sigma-Aldrich) for 20 min.…”