The role of P2X4 receptors of the dorsal root ganglia in the development of chronic hyperalgesia

Author(s)

Glaucilene Ferreira Catroli

• Document type: Doctoral Thesis
• Press: Campinas, SP.
• Institution: Universidade Estadual de Campinas (UNICAMP). Instituto de Biologia
• Defense date: 2020-06-24

Examining board members

Carlos Amílcar Parada; Maria Cláudia Gonçalves de Oliveira; Morena Brazil Martins Sant'Anna; Celina Monteiro da Cruz Lotufo; Alexandre Leite Rodrigues de Oliveira

• Advisor: Carlos Amílcar Parada

Abstract

Understanding the complex molecular mechanisms involved in the genesis of chronic pain is a major challenge to the development of new pain-relieving drugs with minimum side effects. Although the onset of chronic hyperalgesia may be related to either an inflammatory stimulus or a neuronal injury, both events culminate with the sensitization of nociceptors associated with both C- and A? fibers. Regardless of the initial stimulus, the relationship between purinergic signaling and pain is very well characterized in several inflammatory and neuropathic pain models. This is the case of the P2X4 subtype (P2X4R), which activation in microglial cells of the central nervous system is crucial to the development of neuropathic pain. However, in the peripheral nervous system, the effect of P2X4R activation has been scarcely studied. Our group demonstrated that P2X4R antagonism in the dorsal root ganglion (DRG) reverses hyperalgesia in a rat model with diabetic neuropathy but is ineffective in the treatment of acute inflammatory hyperalgesia. Thus, aiming to understand whether the activity of P2X4R in DRG could be related only to chronic pain, we investigated the participation of P2X4R in DRG in the development of acute and chronic hyperalgesia induced either by neuropathic (antineoplastic paclitaxel) or pro-inflammatory mediators (Prostaglandin E2 - PGE2 and carrageenan). Here, we demonstrated that P2X4R were localized in both C- and A-fiber neurons and satellite glial cells of DRG. P2X4R expression was increased in paclitaxel-treated male rats and their knockdown by ASODN, as well as ganglionic treatment with a selective antagonist, reversed paclitaxelinduced neuropathic hyperalgesia (acute and chronic), but not PGE2- or carrageenaninduced inflammatory one. There is sexual dimorphism related to P2X4R activation: females respond equally to paclitaxel administration, but do not increase the expression of these receptors in the DRG; the P2X4R knockdown did not reverse neuropathic hyperalgesia either. There are indications that A-fibers are the main responsible for paclitaxel-induced hyperalgesia since, after desensitization of C-fibers, neuropathic but not inflammatory pain was sustained. Finally, our results show that P2X4Rs is more functional in a neuropathy model than in those in which hyperalgesia arises after an inflammatory stimulus. This finding indicates that the pro-nociceptive neuroplasticity mechanisms involving this receptor differ according to the sex and the triggering stimulus (AU)

• FAPESP's process: 16/23535-5 - The Role of P2X4 receptors of the dorsal root ganglia in the development of chronic hyperalgesia
• Grantee: Glaucilene Ferreira Catroli
• Support Opportunities: Scholarships in Brazil - Doctorate