cGMP signalling in pain processing and regeneration after peripheral nerve injury

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Painful stimuli are detected by sensory neurons whose cell somata are located in dorsal root ganglia and trigeminal ganglia. Previous studies in our and other labs revealed that pain processing in sensory neurons is associated with cGMP production, activation of cGMP-dependent protein kinase I (cGKI) and phosphorylation of cysteine-rich protein 4 (CRP4; formerly named CRP2). Recently, we observed that CRP4 phosphorylation in sensory neurons is evoked by C-type natriuretic peptide (CNP), but not by atrial natriuretic peptide (ANP) or NO, suggesting that a CNP/GC-B/cGMP/cGKI/CRP4 signalling pathway contributes to pain processing in this neuronal population. Using conditional knockout mice with a sensory neuron-specific deletion of GC-B, cGKI or CRP4, we will investigate the in vivo function of this signalling pathway during chronic pain induced by sciatic nerve crush injury, a model that involves degeneration and regeneration of primary afferent neurons. In particular, we will characterize the localization of CNP- and GC-B-positive cell populations in the nociceptive system, the kinetics of CNP release, the spatiotemporal dynamics of cGMP production in dorsal root ganglia after painful stimulation, and downstream mechanisms of this signalling pathway. After elucidation of the localization of CNP-expressing cells in the nociceptive system, we also plan to characterize tissue-specific CNP knockout mice in this context. In contrast to the signalling pathway mentioned above, NO-GC is not expressed in sensory neurons but in satellite glial cells that cover the surface of sensory neurons. Several studies demonstrated that after peripheral nerve injury, satellite glial cells proliferate and contribute to pain processing. Considering that NO synthase expression is markedly upregulated in sensory neurons after peripheral nerve injury, it is very likely that NO acts as a paracrine messenger to increase cGMP production in satellite glial cells. This neuron-glia crosstalk might contribute to the proliferation of satellite cells and their protective role to prevent loss of sensory neurons after peripheral nerve injury. However, the relative contribution of NO-GC isoforms in satellite glial cells and other cells of the nociceptive system to pain processing and regeneration after peripheral nerve injury is poorly understood. We will therefore investigate the in vivo functions of NO-GC signalling during chronic pain induced by sciatic nerve crush injury using conditional knockout mice lacking NO-GC isoforms. Altogether, this project will provide more information on how different cGMP signalling pathways contribute to pain processing and regeneration after nerve injury. The long-term goal is to find out whether targeting cGMP signalling could serve as a new approach for treatment of chronic pain.