Spinal circuits underlying pathological pain (360G-Wellcome-219433_Z_19_Z)

Allodynia and hyperalgesia occur in neuropathic and inflammatory pain states, and depend on circuits involving dorsal horn excitatory interneurons. Recent studies have identified several neurochemical/transcriptomic populations among these cells. We will use a multi-disciplinary approach, involving molecular-genetic targeting of these populations, to investigate their involvement in pain mechanisms at circuit and behavioural levels. We have found that neurons expressing gastrin releasing peptide receptor (GRPR) correspond to vertical cells, which transmit information to lamina I projection neurons, and are implicated in both neuropathic and inflammatory pain. We will use anatomical, electrophysiological and behavioural approaches to determine whether the GRPR cells fulfil this role. If not, we will investigate another population defined by expression of neuropeptide FF. Cells with PKCgamma are critical for neuropathic allodynia, but these can be assigned to two populations that express neurotensin or cholecystokinin. We will determine whether these are functionally different, and whether both contribute to allodynia. Finally, we will establish whether any other excitatory interneurons are interposed between PKCgamma cells and vertical cells in the pathway for tactile allodynia. The study will provide important information about synaptic circuits for pain, and the roles of different interneuron populations. Keywords: pain, spinal cord, neuronal silencing, chemogenetics, optogenetics