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Exogenous or endogenous neuropeptide Y (NPY) acts at its cognate Y1 receptor in dorsal horn to tonically inhibit signs of inflammatory and neuropathic pain. The actions of NPY at the Y2 receptor (Y2R) on thinly myelinated primary afferent neurons are not as clear. To address this gap, we first asked whether intrathecal administration of the Y2R selective agonist, PYY3-36, would reduce behavioral signs of persistent pain after plantar incision or spared nerve injury (SNI) in male and female C57BL/6 mice. PYY3-36 had minimal effect on either mechanical or thermal hypersensitivity when tested 2 days after incision or 14 days after SNI. This unexpected result could be attributed to endogenous NPY release and saturation of Y2Rs leading to unavailability of Y2Rs to bind to exogenous Y2 agonists. To begin to test this idea, we intrathecally administered the Y2R antagonist BIIE0246 in naïve mice. BIIE0246 did not change heat hypersensitivity or motor coordination, but dose-dependently (0.01-3µg) elicited robust pain-like behaviors including mechanical and cold hypersensitivity. BIIE024 also elicited itch-like behaviors including scratching and back biting. To determine whether these effects were mediated by Y2Rs in dorsal root ganglion (DRG) neurons, we crossed Pirtcre mice with Npy2rlox/lox mice to create Npy2RDRG-/- conditional knockout mice. Npy2RDRG-/- mice expressed Y2 protein in hippocampus but not DRG. BIIE0246 (3µg, i.t.) induced pain- and itch-like behaviors in Npy2rlox/lox controls but not in Npy2RDRG-/- mice. Npy2RDRG-/- mice exhibited less mechanical and thermal hypersensitivity as compared to Npy2rlox/lox controls in the SNI model of neuropathic pain and the plantar incision latent sensitization model of chronic postoperative pain. Together, our findings suggest that Y2Rs on primary afferent neurons exert two functions: 1) tonic inhibition of nociception and itch in the absence of injury; and 2) facilitate persistent pain in the setting of nerve or tissue injury. Grant support from R01NS45954, R01NS62306, and R01DA37621 awarded to Bradley K. Taylor.
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