Pharmacology and spinal microcircuitry of neuropeptide Y receptors.
Chronic neuropathic pain affects 7-10% of the general population. Quality of life is severely impaired due to increased drug prescriptions, visits to health care providers, and comorbidities, including anxiety and depression. Thus, there is a critical and pressing need to develop safe, nonaddictive, and efficacious analgesic drugs for neuropathic pain. This requires a better understanding of its mechanisms, which generally include alterations in ion channels and G-protein-coupled receptor, imbalances between excitatory and inhibitory signaling, and plasticity in the CNS. We and many others are working to understand these mechanisms in animal models, identify novel therapeutic targets, and then translate this knowledge to the development of new analgesic drugs for clinical practice. To this end, we have spent over 25 years studying the neuropeptidergic inhibition of spinal pain transmission with the aim to develop analgesic drugs that will target the NPY Y1 receptor in the dorsal horn. The Taylor lab’s initial R01 work (2001-2007) indicated that intrathecal administration of NPY acts in a dose- and receptor-dependent manner to reduce behavioral signs of inflammatory pain and peripheral neuropathic pain, setting the stage to determine the therapeutic potential of NPY ligands for chronic pain. During the 2nd phase of funding (2018-2014), they discovered that an injury-induced enhancement of endogenous NPY-Y1 receptor GPCR signaling could be maintained long enough to confine chronic inflammatory and neuropathic pain within a state of remission (Solway et al., PNAS, 2011). These findings provided a new approach to prevent or alleviate chronic pain: by facilitating endogenous NPY receptor analgesia in the CNS and maintain latent sensitization in remission. The third funding period (2015-2020) found that injury induces a sustained spinal release of NPY, leading to the inhibition of pronociceptive Npy1r-expressing interneurons in the dorsal horn. During the fourth and current funding period (2021-2026), they are implementing transformative neuroscience and biomedical research approaches such as Cre-lox and FLP-FRT recombination technology to study how subpopulations of Npy1r-expressing neurons contribute to the microcircuitry of chronic pain modulation in the dorsal horn (Nelson et al., PNAS, 2022).