Response to DOR Agonist in Non-Inflammatory and Inflammatory Pain
In an incompetent state, A-kinase anchoring protein (AKAP) scaffolds protein kinase A (PKA), increasing its activity. Tethered to the plasma membrane, PKA actively phosphorylates g protein-coupled receptor kinase 2 (GRK2), which drives it to constitutively associate with membrane-bound delta opioid receptor (DOR). The protein-protein interaction between DOR and GRK2, hinders receptor coupling to G proteins. Consequently, there is no DOR-mediated Gβγ inhibition voltage-gated calcium channels (VGCCs).
In the context of inflammatory priming, bradykinin (BK) activates bradykinin receptor type 2 (B2R) to stimulate the phospholipase C (PLC)-protein kinase C (PKC) pathway. Activated PKC phosphorylates raf kinase inhibitory protein (RKIP), which self-dimerizes and sequesters GRK2 to the cytosolic compartment. Unbound to GRK2, activated DOR couples to G proteins to inhibit calcium influx through VGCCs.
Non-Inflammatory Pain + Paroxetine.
Paroxetine (PRX), a direct inhibitor of GRK2, binds the kinase at its active site. This prevents PKA-dependent phosphorylation of GRK2 and, thus, reduces the constitutive interaction between DOR and GRK2. No longer bound to GRK2, activated DOR can optimally couple to its G proteins to inhibit calcium influx through VGCCs.