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The role of purinergic receptor P2X4 signaling of dorsal root ganglia and spinal cord in early and late phase allodynia in the K/BxN mouse model of chronic inflammation

Grant number: 18/05778-3
Support type:Scholarships abroad - Research Internship - Doctorate
Effective date (Start): July 30, 2018
Effective date (End): July 29, 2019
Field of knowledge:Biological Sciences - Physiology - General Physiology
Principal Investigator:Carlos Amilcar Parada
Grantee:Glaucilene Ferreira Catroli
Supervisor abroad: Tony L. Yaksh
Home Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
Local de pesquisa : University of California, San Diego (UC San Diego), United States  
Associated to the scholarship:16/23535-5 - The Role of P2X4 receptors of the dorsal root ganglia in the development of chronic hyperalgesia, BP.DR

Abstract

When an intense stimulus results in tissue injury or inflammation, the associated pain is characterized by an ongoing pain sensation and appearance of enhanced response to mild noxious or non-aversive stimuli reflecting states of hyperalgesia and allodynia, respectively. Typically, these exaggerated pain states resolve with resolution of the inflammation or wound healing. However, there are several conditions in which the pain state may transition to a chronic state and the enhanced pain behavior may persist even after the healing of the wound or resolution of the inflammation. One animal model that has been particularly useful to investigate this pain related mechanism is the K/BxN serum transfer arthritis model, which share similarities to human rheumatoid arthritis. The injection of serum from the K/BxN mice with antibodies against glucose-6- phosphate isomerase into a normal mouse induces immune complex-mediated transient inflammatory arthritis in the recipient. The inflammatory state lasts approximately 15-20 days and, a significant tactile allodynia begins by 1-2 days and continues long after the inflammatory component has resolved, that is, there is a transition from an acute inflammation to a post-inflammatory condition. Based on its differential immunohistochemical phenotype and analgesic efficacy it has been proposed that the post-inflammatory phase has a with a neuropathic phenotype. Work with mutant mice and intrathecal drug delivery, it has been concluded that the evolution of the chronic component of the K/BxN allodynia reflects the role of innate immunity signaling through Toll-like Receptors 4 (TLR4) activation. Purinergic receptors (P2XR) have also been implicated in the development and maintenance of several pain states. The P2X4 receptor subtype, specifically, plays an important role in the pain phenotype observed after peripheral nerve injury-induced pain, where hypersensitivity appears to depend on ongoing purinergic signaling through microglial P2X4R activation. Interestingly, it has been demonstrated that increased expression of P2X4 in microglia occurs after activation of TLR4. All of these data underly the hypothesis of my research that TLR4 signaling mediates the transition from the acute inflammatory pain state to the chronic post inflammatory state with a neuropathic phenotype through an enhanced expression of P2X4 receptors in dorsal horn and DRG neuron and glia. Accordingly, this work will investigate the role of the purinergic receptor P2X4 signaling in early (inflammatory) and late (chronic) phase allodynia in the k/BxN mouse model of persistent inflammation and its relation with the TLR4 receptors. Understanding the TLR4-P2X4 signaling cascade in this transition from an acute inflammation to a post-inflammatory chronic condition will represent an important advance towards the development of future therapies that regulate this cascade.