Modulation of TRPV1, nociceptor sensitization , and induction of thermal hyperalgesia by C-type natriuretic peptide

Abstract

Rheumatoid arthritis (RA) is caused by aberrant attack of the joints by native inflammatory system. This can lead to joint destruction and pain that can be debilitating. Increased angiogenesis and innervation by nociceptive afferent fibers are characteristic features of RA joints, which in addition to the elevated levels of a wide variety of inflammatory mediators, are thought to play an important role in the pathogenesis of chronic inflammatory pain associated with RA. Interestingly, a recent report indicates that C-type natriuretic peptide (CNP) is increased in the blood serum of RA patients. Natriuretic peptides (NPs) control natriuresis and normalize changes in blood pressure. Many biological effects of NPs are mediated by guanylate cyclase (GC)-coupled NP receptors, NPR-A and NPR-B, whereas the third NP receptor, NPR-C, lacks the GC kinase domain and acts as the NP clearance receptor. In addition, NPR-C can couple to specific Gαi-βγ-mediated intracellular signaling cascades in numerous cell types. Recent studies suggest that NPs are also involved in the regulation of pain sensitivity, although the underlying mechanisms remain largely unknown. In Aim 1, I show that CNP acutely sensitized the excitation of mouse dorsal root ganglia (DRG) sensory neurons that is dependent on the transient receptor potential vanilloid-1 (TRPV1). CNP potentiated capsaicinand proton-activated TRPV1 currents in cultured mouse DRG neurons and increased neuronal firing frequency, an effect that was absent in DRG neurons from TRPV1 mice. Further, CNP injection into mouse hind paw led to the development of thermal hyperalgesia, which was absent in TRPV1 mice. In Aim 2, I dissected the signaling mechanism underlying TRPV1 sensitization by CNP. My results show that all 3 functional NPRs are expressed in mouse DRG neurons;