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Identification of GRPR and MOR1Y isomers responsible for opioid-induced pruritus: studies in human spinal cord tissue.
Abstract Number: BP-3
Abstract Type: Original Research
Background: We previously demonstrated in mice that spinal opioids induce pruritus by activating spinal gastrin releasing peptide receptor (GRPR) pathways which interact with a mu-opioid receptor isomer (MOR-1D) specific for opioid-induced pruritus. We synthesized a MOR-1D targeted fusion peptide which completely eradicated scratching following spinal morphine. These findings have not been extrapolated to clinical practice because spinal cord MOR isomers and GRPR have not been reported in humans. Here we identify/sequence the different human MOR isomers, identify a specific isomer that interacts with GRPR and produce a peptide to inhibit its activity.
Methods: Specimens of spinal cord were obtained from fresh human cadavers. Functional interactions between hGRPR and different human Oprm1 C terminal splicing variants were assessed using free cytosolic calcium concentration imaging (F340/F380) in HEK 293 cells.
Results: Of 10 splicing variants, only hMOR1B1 and hMOR1Y cross-activated calcium signaling of hGRPR upon morphine incubation (Fig A). Morphine failed to evoke calcium responses when cells were pre-incubated with naltrexone (Fig B), or were singly transfected with hMOR1B1, hMOR1Y or hGRPR. We synthesized Tat-fusion peptides for the unique C terminal tip of hMOR1B1 and hMOR1Y. Pre-incubation of Tat-hMOR1Y for 2 h dose-dependently blocked morphine-induced calcium spikes in hGRPR/hMOR1Y-transfected cells (Fig C,D), while Tat-hMOR1B1 had no effect. Tat-hMOR1Y also dose-dependently attenuated morphine-induced scratching behaviors in mice (Fig E). Reverse transcriptase-PCR on the human spinal cord samples revealed PCR bands corresponding to hMOR1, hMOR1A, hMOR1B5, and hMOR1Y isomers in the dorsal horn of the spinal cord (Fig F). The anatomic location of hMOR1Y expression and its interactions with hGRPR suggest an important roles in morphine-induced pruritus.
Conclusions: Here we identify for the first time the sequences of the isomers of the human spinal cord MOR. Assessment of the free cytosolic calcium concentration in transfected HEK cells showed that the human MOR-1Y isomer is activated by both morphine and GRP, and that a peptide targeting the MOR-1Y isomer can completely abolish the opioid-induced calcium spike. Furthermore, this peptide targeting the human isomer can selectively abolish opioid-induced scratching behaviours in mice. We hope this information will open a path to developing a pharmacological solution to spinal opioid induced pruritus.