Retrograde signaling in the central processes of primary sensory neurons: the influence of activity in the central nervous system on gene expression in peripheral neurons. (360G-Wellcome-086892_Z_08_Z)

Neuropathic pain caused by damage to the peripheral nerve has proved difficult to manage clinically. In part this is because research has implicated plasticity in both peripheral neurons and central pathways. We propose that neuropathic pain following peripheral nerve damage is maintained by a direct action of descending spinal pathways on both dorsal horn neurons and primary afferent fibers terminating within the dorsal horn. Our hypothesis is in two parts. First, that investigating molecular changes in the dorsal horn following manipulation of the descending pathways will uncover novel targets for the treatment of chronic pain conditions and second, that there is a two-way communication between the peripheral nerve and the central nervous system and that central neuronal changes drive long-term molecular changes in subsets of primary afferents thus increasing their sensitivity and maintaining the painful neuropathy. We therefore i) aim to identify gene transcripts in the dorsal horn and dorsal root ganglion that are regulated following central manipulations of descending pathways, ii) investigate retrograde signaling in dorsal roots, particularly CREB and CREB2, and their modulation by central processes.