cGMP signaling in pain processing and regeneration after peripheral nerve injury

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Chronic pain is a highly prevalent and poorly managed health problem. Unraveling the molecular mechanisms underlying pain processing is a crucial prerequisite for the rational development of novel analgesic drugs. Previous studies in our and other labs revealed that pain processing is associated with cGMP production in the nociceptive system. There is accumulating evidence that cGMP production during chronic pain is not only initiated by nitric oxide (NO) but also by natriuretic peptides (NP). However, the cellular distribution and the functional impact of NO- and NP-dependent cGMP production in this context remains elusive. In the previous funding period, we found that the two isoforms of ‘soluble’, NO-sensitive guanylyl cyclase (NO-GC1 and NO-GC2) are localized to distinct subpopulations of interneurons in the spinal cord. Interestingly, NO-GC1 contributes to the processing of neuropathic pain after peripheral nerve injury, whereas NO-GC2 modulates the processing of inflammatory pain. Moreover, we found that NP may initiate cGMP production in NO-GC-negative neurons of the nociceptive system. Based on our previous work and recently established tissue-specific conditional mouse lines, we will now extend our studies to learn more about the mechanisms underlying NO- and NP-dependent cGMP signaling during chronic pain. The major aims that will be approached are (1) to characterize downstream targets of NO/cGMP signaling in spinal interneurons during neuropathic pain after peripheral nerve injury, (2) to determine the impact of particulate guanylyl cyclases in sensory neurons on pain processing and nerve regeneration, and (3) to elucidate the mechanisms leading to NP release in the nociceptive system. Altogether, this project will provide more information on how different cGMP signaling pathways contribute to pain processing. The long-term goal is to find out whether targeting cGMP signaling could serve as a new pharmacological approach for treatment of pain.