The role of crotalphine in the primary cilium dynamics of primary afferent neurons: novel insights for the study of analgesic compounds

Abstract

Chronic pain affects around 30% of the world's population. The treatment for this condition is still a challenge, becoming interesting the study of new drugs and new molecular targets capable to modulate the nociceptive system. Crotalphine is a peptide isolated from the South American Crotalus durissus terrificus snake venom, which synthetic analog has long-acting analgesic action in acute and chronic pain models (patent PI 0502399-8 granted 05/05/2018). Studies developed by our group have identified part of the mechanisms responsible for this effect, but its cellular/molecular target as well as its mechanism of action in peripheral neurons is not completely clear. It is known that the vast majority of cells, including neurons, have on their surface a cellular "nano-antenna" called primary cilium. For a long time, this cilium was considered a vestigial organelle, but its role in the transduction of extracellular stimuli has been proven for the last 15 years. It is known that the Wnt signaling pathway and the structural stability of the microtubules are directly related to the functionality of the primary cilium. However, so far, the function of this organelle in mammalian peripheral nervous system neurons as well as their importance in modulating painful states is unclear. Since crotalphine modulates the Wnt signaling and stabilizes the cytoskeleton of neurons upon inflammatory stimulation, the aims of this work are to evaluate the role of crotalphine in the primary cilium dynamics of primary afferent neurons in the presence of noxious stimuli and to verify the importance of this organelle in analgesia induced by crotalphine in vivo. In this way, we hope that the results of this project may open new perspectives on the mechanisms of action of crotalphine, as well as assigning the primary cilium an unprecedented cellular target for the study of toxins and analgesic compounds. (AU)