The pharmacotherapeutic potential of neuropeptide Y for chronic pain

Chronic pain is a major medical problem that requires new therapeutic options. Discovered by Victor Mutt in 1982, neuropeptide Y (NPY) is rapidly emerging as a master regulator of pain relief. Genetic knockdown of NPY or pharmacological inhibition of its receptors demonstrates that NPY signaling tonically inhibits indices of chronic inflammatory and neuropathic pain. Primary targets of NPY analgesia include neurons in the dorsal horn of the spinal cord and the parabrachial nucleus of the brain that express the Npy1r (Y1) receptor. NPY signaling is enhanced following injury, and endogenous analgesic synergy between Y1 receptors and mu opioid receptors maintain chronic pain sensitization in a latent state of remission. We propose that disruptions to endogenous NPY analgesia may mediate pathological transitions from acute to chronic pain, which could be treated by CNS administration of Y1 agonists or Npy2r (Y2) agonists or antagonists, depending on the pain state. Chemogenetic manipulations or targeted ablations in rodent models of chronic inflammation or peripheral nerve injury establish that spinal Y1-interneurons are necessary and sufficient to elicit behavioral signs of both the sensory and affective dimensions of pain. Transcriptomic and in situ hybridization studies revealed three primary subpopulations of spinal Y1-interneurons that are conserved in higher order mammals, including non-human primates and humans. Spinally directed (intrathecal) administration of Y1-selective pharmacological agonists inhibit pronociceptive neurons that co-express Y1 and gastrin-releasing peptide to inhibit neuropathic pain. To circumvent highly invasive administration routes, ongoing studies are leveraging the intranasal route for delivery of NPY into the brain.