The role of kinin B1 and B2 receptors in the persistent pain induced by experimental autoimmune encephalomyelitis (EAE) in mice: Evidence for the involvement of astrocytes

• Published in: Neurobiology of disease 2013-06, Vol.54, p.82-93
• Main Authors: Dutra, Rafael C, Bento, Allisson F, Leite, Daniela F.P, Manjavachi, Marianne N, Marcon, Rodrigo, Bicca, Maíra Assunção, Pesquero, João B, Calixto, João B
• Format: Article
• Language: English
• Subjects: Animal models; Animals; Astrocytes - metabolism; Autoimmunity; Blotting, Western; Bradykinin B1 and B2 receptors; Demyelination; EAE; Encephalomyelitis, Autoimmune, Experimental - complications; Encephalomyelitis, Autoimmune, Experimental - metabolism; Female; Hyperalgesia - etiology; Hyperalgesia - metabolism; Immunohistochemistry; Mice; Mice, Inbred C57BL; Mice, Knockout; Multiple sclerosis; Neuralgia - metabolism; Neurology; Neuropathic pain; Real-Time Polymerase Chain Reaction; Receptor, Bradykinin B1 - metabolism; Receptor, Bradykinin B2 - metabolism
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2013.02.007

Abstract Multiple sclerosis (MS) is a progressive, demyelinating inflammatory disease of the human central nervous system (CNS). While the primary symptoms of MS affect motor function, it is now recognized that chronic pain is a relevant symptom that affects both animals and MS patients. There is evidence that glial cells, such as astrocytes, play an important role in the development and maintenance of chronic pain. Kinins, notably bradykinin (BK) acting through B1 (B1 R) and B2 (B2 R) receptors, play a central role in pain and inflammatory processes. However, it remains unclear whether kinin receptors are involved in neuropathic pain in MS. Here we investigated by genetic and pharmacological approaches the role of kinin receptors in neuropathic pain behaviors induced in the experimental autoimmune encephalomyelitis (EAE) mouse model. Our results showed that gene deletion or antagonism of kinin receptors, especially B1 R, significantly inhibited both tactile and thermal hypersensitivity in EAE animals. By contrast, animals with EAE and treated with a B1 R selective agonist displayed a significant increase in tactile hypersensitivity. We also observed a marked increase in B1 R mRNA and protein level in the mouse spinal cord 14 days after EAE immunization. Blockade of B1 R significantly suppressed the levels of mRNAs for IL-17, IFN-γ, IL-6, CXCL-1/KC, COX-2 and NOS2, as well as glial activation in the spinal cord. Of note, the selective B1 antagonist DALBK consistently prevented IFN-induced up-regulation of TNF-α and IL-6 release in astrocyte culture. Finally, both B1 R and B2 R antagonists significantly inhibited COX-2 and NOS2 expression in primary astrocyte culture. The B1 R was co-localized with immunomarker of astrocytes in the spinal cord of EAE-treated animals. The above data constitute convincing experimental evidence indicating that both kinin receptors, especially the B1 subtype, exert a critical role in the establishment of persistent hypersensitivity observed in the EAE model, an action that seems to involve a central inflammatory process, possibly acting on astrocytes. Thus, B1 selective antagonists or drugs that reduce kinin release may have the potential to treat neuropathic pain in patients suffering from MS.